Substituted arylamine derivatives and methods of use

ABSTRACT

Selected compounds are effective for prophylaxis and treatment of diseases, such as angiogenesis mediated diseases. The invention encompasses novel compounds, analogs, prodrugs and pharmaceutically acceptable derivatives thereof, pharmaceutical compositions and methods for prophylaxis and treatment of diseases and other maladies or conditions involving, cancer and the like. The subject invention also relates to processes for making such compounds as well as to intermediates useful in such processes.

[0001] This application is a continuation-in-part of U.S. patentapplication Ser. No. 10/046,526 filed Jan. 10, 2002 claiming the benefitof U.S. Provisional Application Nos. 60/261,360, filed Jan. 12, 2001,and 60/323,686 filed Sep. 19, 2001, which are hereby incorporated byreference.

FIELD OF THE INVENTION

[0002] This invention is in the field of pharmaceutical agents andspecifically relates to compounds, compositions, uses and methods fortreating cancer and angiogenesis-related disorders.

BACKGROUND OF THE INVENTION

[0003] Protein kinases represent a large family of proteins which play acentral role in the regulation of a wide variety of cellular processes,maintaining control over cellular function. A partial list of suchkinases includes abl, Akt, bcr-ab1, Blk, Brk, Btk, c-kit, c-met, c-src,CDK1, CDK2, CDK3, CDK4, CDK5, CDK6, CDK7, CDK8, CDK9, CDK10, cRaf1,CSF1R, CSK, EGFR, ErbB2, ErbB3, ErbB4, Erk, Fak, fes, FGFR1, FGFR2,FGFR3, FGFR4, FGFR5, Fgr, flt-1, Fps, Frk, Fyn, Hck, IGF-1R, INS-R, Jak,KDR, Lck, Lyn, MEK, p38, PDGFR, PIK, PKC, PYK2, ros, tie, tie2, TRK,Yes, and Zap70. Inhibition of such kinases has become an importanttherapeutic target.

[0004] Certain diseases are known to be associated with deregulatedangiogenesis, for example ocular neovascularisation, such asretinopathies (including diabetic retinopathy), age-related maculardegeneration, psoriasis, hemangioblastoma, hemangioma, arteriosclerosis,inflammatory disease, such as a rheumatoid or rheumatic inflammatorydisease, especially arthritis (including rheumatoid arthritis), or otherchronic inflammatory disorders, such as chronic asthma, arterial orpost-transplantational atherosclerosis, endometriosis, and neoplasticdiseases, for example so-called solid tumors and liquid tumors (such asleukemias).

[0005] At the center of the network regulating the growth anddifferentiation of the vascular system and its components, both duringembryonic development and normal growth, and in a wide number ofpathological anomalies and diseases, lies the angiogenic factor known asVascular Endothelial Growth Factor”(VEGF; originally termed “VascularPermeability Factor”, VPF), along with its cellular receptors (see G.Breier et al., Trends in Cell Biology, 6, 454-6 (1996)).

[0006] VEGF is a dimeric, disulfide-linked 46-kDa glycoprotein relatedto “Platelet-Derived Growth Factor” (PDGF); it is produced by normalcell lines and tumor cell lines; is an endothelial cell-specificmitogen; shows angiogenic activity in in vivo test systems (e.g. rabbitcornea); is chemotactic for endothelial cells and monocytes; and inducesplasminogen activators in endothelial cells, which are involved in theproteolytic degradation of extracellular matrix during the formation ofcapillaries. A number of isoforms of VEGF are known, which showcomparable biological activity, but differ in the type of cells thatsecrete them and in their heparin-binding capacity. In addition, thereare other members of the VEGF family, such as “Placenta GrowthFactor”(PlGF) and VEGF-C.

[0007] VEGF receptors (VEGFR) are transmembranous receptor tyrosinekinases. They are characterized by an extracellular domain with sevenimmunoglobulin-like domains and an intracellular tyrosine kinase domain.Various types of VEGF receptor are known, e.g. VEGFR-1 (also known asflt-1), VEGFR-2 (also known as KDR), and VEGFR-3.

[0008] A large number of human tumors, especially gliomas andcarcinomas, express high levels of VEGF and its receptors. This has ledto the hypothesis that the VEGF released by tumor cells stimulates thegrowth of blood capillaries and the proliferation of tumor endotheliumin a paracrine manner and through the improved blood supply, acceleratetumor growth. Increased VEGF expression could explain the occurrence ofcerebral edema in patients with glioma. Direct evidence of the role ofVEGF as a tumor angiogenesis factor in vivo is shown in studies in whichVEGF expression or VEGF activity was inhibited. This was achieved withanti-VEGF antibodies, with dominant-negative VEGFR-2 mutants whichinhibited signal transduction, and with antisense-VEGF RNA techniques.All approaches led to a reduction in the growth of glioma cell lines orother tumor cell lines in vivo as a result of inhibited tumorangiogenesis.

[0009] Angiogenesis is regarded as an absolute prerequisite for tumorswhich grow beyond a diameter of about 1-2 mm; up to this limit, oxygenand nutrients may be supplied to the tumor cells by diffusion. Everytumor, regardless of its origin and its cause, is thus dependent onangiogenesis for its growth after it has reached a certain size.

[0010] Three principal mechanisms play an important part in the activityof angiogenesis inhibitors against tumors: 1) Inhibition of the growthof vessels, especially capillaries, into avascular resting tumors, withthe result that there is no net tumor growth owing to the balance thatis achieved between cell death and proliferation; 2) Prevention of themigration of tumor cells owing to the absence of blood flow to and fromtumors; and 3) Inhibition of endothelial cell proliferation, thusavoiding the paracrine growth-stimulating effect exerted on thesurrounding tissue by the endothelial cells which normally line thevessels. See R. Connell and J. Beebe, Exp. Opin. Ther. Patents, 11,77-114 (2001).

[0011] VEGF's are unique in that they are the only angiogenic growthfactors known to contribute to vascular hyperpermeability and theformation of edema. Indeed, vascular hyperpermeability and edema that isassociated with the expression or administration of many other growthfactors appears to be mediated via VEGF production.

[0012] Inflammatory cytokines stimulate VEGF production. Hypoxia resultsin a marked upregulation of VEGF in numerous tissues, hence situationsinvolving infarct, occlusion, ischemia, anemia, or circulatoryimpairment typically invoke VEGF/VPF-mediated responses. Vascularhyperpermeability, associated edema, altered transendothelial exchangeand macromolecular extravasation, which is often accompanied bydiapedesis, can result in excessive matrix deposition, aberrant stromalproliferation, fibrosis, etc. Hence, VEGF-mediated hyperpermeability cansignificantly contribute to disorders with these etiologic features. Assuch, regulators of angiogenesis have become an important therapeutictarget.

[0013] Schipper U.S. Pat. No. 3,226,394, issued Dec. 28, 1965, describesanthranilamides as CNS depressants. Japanese patent JP2000256358describes pyrazole derivatives that block the calcium release-activatedcalcium channel. EP application 9475000, published Oct. 6, 1999,describes compounds as PGE₂ antagonists. PCT publication WO96/41795,published Dec. 27, 1996, describes benzamides as vasopressinantagonists. WO01/29009 describes aminopyridines as KDR inhibitors.WO01/30745 describes anthranilic acids as CGMP phosphodiesteraseinhibitors. WO00/02851, published Jan. 20, 2000 descxribesarylsulfonylamnoaryl amides as guanylate cyclase activators. WO98/45268describes nicotinamide derivatives as PDE4 inhibitors. WO98/24771describes benzamides as vasopressin antagonists.

[0014] U.S. Pat. No. 5,532,358, issued Jul. 2, 1996, describes thepreparation of2-(cyclopropylamino)-N-(2-methoxy-4-methyl-3-pyridinyl)-3-pyridinecarboxamideas an intermediate for HIV inhibitors. Triazine-substituted amines aredescribed for their aggregating ability (J. Amer. Chem. Soc., 115,905-16 (1993). Substituted imidazolines were tested for theirantidepressant activity in Ind. J. Het. Chem., 2, 129-32 (1992).N-(4-Pyridyl)anthranilic amides were described in Chem Abstr. 97:109837(1981). PCT publication WO99/32477, published Jul. 1, 1999, describesanthranilamides as anti-coagulants. U.S. Pat. No. 6,140,351 describesanthranilamides as anti-coagulants. PCT publication WO99/62885,published Dec. 9, 1999, describes 1-(4-aminophenyl)pyrazoles asantiinflammatories. PCT publication WO00/39111, published Jul. 6, 2000,describes amides as factor Xa inhibitors. PCT publication WO00/39117,published Jul. 6, 2000, describes heteroaromatic amides as factor Xainhibitors. PCT publication WO00/27819, published May 18, 2000,describes anthranilic acid amides as VEGF inhibitors. PCT publicationWO00/27820 published May 18, 2000, describes N-aryl anthranilic acidamides as VEGF inhibitors. 7-Chloroquinolinylamines are described inFR2168227 as antiinflammatories. WO01/55114, published Aug. 2, 2001,describes nicotinamides for the treatment of cancer. WO01/55115,published Aug. 2, 2001, describes nicotinamides for the treatment ofapoptosis. WO01/85715, published Nov. 15, 2001, describes substitutedpyridines and pyrimidines as anti-angiogenesis agents. PCT publicationWO01/85691 published Nov. 15, 2001, describes anthranilic amides as VEGFinhibitors. PCT publication WO01/85671 published Nov. 15, 2001,describes anthranyl amides as VEGF inhibitors. PCT publicationWO01/81311 published Nov. 1, 2001, describes anthranilic amides as VEGFinhibitors. However, compounds of the current invention have not beendescribed as inhibitors of angiogenesis such as for the treatment ofcancer.

DESCRIPTION OF THE INVENTION

[0015] A class of compounds useful in treating cancer and angiogenesisis defined by Formula I

[0016] wherein each of A¹ and A² is independently C or N;

[0017] wherein A¹-A² together are part of a ring A selected from 5- or6-membered heteroaryl, more preferably 5-membered heteroaryl selectedfrom thienyl, oxazolyl, imidazolyl, pyrrolyl, pyrazolyl, isoxazolyl,triazolyl, isothiazolyl, and 6-membered heteroaryl selected frompyridyl, pyrazinyl, pyrimidinyl and pyridazinyl, even more preferablypyridyl or pyrimidinyl, most preferably pyridyl;

[0018] wherein X is selected from

[0019]  more preferably —C(O)—NH—;

[0020] wherein Z is oxygen or sulfur;

[0021] wherein Y is selected from

[0022]  preferably selected from

[0023]  more preferably —NH—CH₂—;

[0024] wherein R^(a) and R^(b) are independently selected from H, halo,and C₁₋₄-alkyl substituted with R¹, or wherein R^(a) and R^(b) togetherform C₃-C₄ cycloalkyl, preferably H, halo, and C₁₋₂-alkyl substitutedwith R¹, or

[0025] wherein R^(a) and R^(b) together form C₃-C₄ cycloalkyl, morepreferably H, halo and C₁-C₂-alkyl, even more preferably H;

[0026] wherein R^(c) is C₁-C₄ alkylenyl, where one of the CH₂ groups maybe substituted with an oxygen atom or an —NH—, preferably C₁-C₂alkylenyl, where one of the CH₂ groups may be substituted with an oxygenatom or an —NH—, more preferably —CH₂—;

[0027] wherein R¹ is one or more substituents independently selectedfrom H, halo, —OR⁷, oxo, —SR⁷, —CO₂R⁷, —COR⁷, —CONR⁷R⁷, —NR⁷R⁷,—SO₂NR⁷R⁷, —NR⁷C(O)OR⁷, —NR⁷C(O)R⁷, cycloalkyl, optionally substitutedphenylalkylenyl, optionally substituted 5-6 membered heterocyclyl,optionally substituted heteroarylalkylenyl, optionally substitutedphenyl, lower alkyl, cyano, lower hydroxyalkyl, lower carboxyalkyl,nitro, lower alkenyl, lower alkynyl, lower aminoalkyl, loweralkylaminoalkyl and lower haloalkyl;

[0028] preferably H, halo, —OR⁷, oxo, —SR⁷, —CO₂R⁷, —CONR⁷R⁷, —COR⁷,—NR⁷R⁷, —SO₂NR⁷R⁷, —NR⁷C(O)OR⁷, —NR⁷C(O)R⁷, cycloalkyl, optionallysubstituted 5-6 membered heterocyclyl, optionally substituted phenyl,C₁-C₂-alkyl, cyano, C₁-C₂-hydroxyalkyl, C₁-C₃-carboxyalkyl, nitro,C₂-C₃-alkenyl, C₂-C₃-alkynyl and C₁-C₂-haloalkyl, more preferably H,halo, —OR⁷, —SR⁷, —CO₂R⁷, —CONR⁷R⁷, —COR⁷, —NR⁷R⁷, —SO₂NR⁷R⁷,—NR⁷C(O)OR⁷, —NR⁷C(O)R⁷, cycloalkyl, optionally substituted 5-6 memberedheterocyclyl, optionally substituted phenyl, C₁₋₂-alkyl, cyano,C₁₋₂-hydroxyalkyl, C₁₋₃-carboxyalkyl, nitro, C₂₋₃-alkenyl, C₂₋₃-alkynyland C₁₋₂-haloalkyl, additionally preferred are H, chloro, fluoro, bromo,amino, hydroxy, methyl, ethyl, propyl, trifluoromethyl, methoxy, ethoxy,trifluoromethoxy, carboxymethyl, unsubstituted or substituted phenyl andunsubstituted or substituted heteroaryl selected from thienyl, furanyl,pyridyl, imidazolyl, and pyrazolyl;

[0029] wherein R² is selected from

[0030] a) substituted or unsubstituted 6-10 membered aryl,

[0031] b) substituted or unsubstituted 5-6 membered heterocyclyl,

[0032] c) substituted or unsubstituted 9-11 membered fused heterocyclyl,

[0033] d) cycloalkyl, and

[0034] e) cycloalkenyl,

[0035] preferably substituted or unsubstituted aryl selected fromphenyl, naphthyl, indenyl and tetrahydronaphthyl, substituted orunsubstituted 5-6 membered heteroaryl, and substituted or unsubstituted9-10 membered fused heteroaryl,

[0036] more preferably phenyl, indazolyl, indolyl,2,1,3-benzothiadiazolyl, isoquinolyl, quinolyl, and quinazolinyl, evenmore preferably phenyl, indazolyl, indolyl, isoquinolyl and quinolyl;

[0037] wherein substituted R² is substituted with one or moresubstituents independently selected from halo, —OR⁷, —SR⁷, —SO₂R⁷,—CO₂R⁷, —CONR⁷R⁷, —COR⁷, —NR⁷R⁷, —SO₂NR⁷R⁷, —NR⁷C(O)OR⁷, —NR⁷C(O)R⁷, —NH(C₁-C₄ alkylenylR⁷), optionally substituted cycloalkyl, optionallysubstituted 5-6 membered heterocyclyl, optionally substituted phenyl,lower alkyl substituted with R¹, cyano, nitro, lower alkenyl and loweralkynyl, preferably halo, —OR⁷, —SR⁷, —SO₂R⁷, —CO₂R⁷, —CONR⁷R⁷, —COR⁷,—NR⁷R⁷, —NH (C₁-C₂-alkylenylR⁷), —(C₁-C₂-alkylenyl) NR⁷R⁷, —SO₂NR⁷R⁷,—NR⁷C(O)OR⁷, —NR⁷C(O)R⁷, optionally substituted cycloalkyl, optionallysubstituted 5-6 membered heterocyclyl, optionally substituted phenyl,optionally substituted phenyl-C₁-C₂-alkylenyl, optionally substituted5-6 membered heterocyclyl-C₁-C₂-alkylenyl, C₁-C₂-alkyl, cyano,C₁-C₂-hydroxyalkyl, nitro and C₁-C₂-haloalkyl, more preferably halo,—OR⁷, —SR⁷, —CO₂R⁷, —CONR⁷R⁷, —COR⁷, —NR⁷R⁷, —NH(C₁-C₂-alkylenyl-R⁷),—(C₁-C₂-alkylenyl) NR⁷R⁷, —SO₂NR⁷R⁷, —NR⁷C(O)OR⁷, —NR⁷C(O)R⁷, optionallysubstituted cycloalkyl, optionally substituted 5-6 memberedheterocyclyl, optionally substituted phenyl, optionally substitutedphenyl-C₁-C₂-alkylenyl, optionally substituted 5-6 memberedheterocyclyl-C₁-C₂-alkylenyl, C₁-C₂-alkyl, cyano, C₁-C₂-hydroxyalkyl,nitro and C₁-C₂-haloalkyl, additionally preferred are chloro, fluoro,amino, hydroxy, cyclohexyl, phenylmethyl, morpholinylmethyl,methylpiperdinylmethyl, methylpiperazinylmethyl, ethyl, propyl,trifluoromethyl, phenyloxy, methoxy and ethoxy;

[0038] wherein R³ is selected from aryl, preferably phenyl;

[0039] wherein R³ is substituted with one or more substituentsindependently selected from halo, —OR⁷, —SR⁷, —CO₂R⁷, —CONR⁷R⁷, —COR⁷,—NR⁷R⁷, —SO₂NR⁷R⁷, —NR⁷C(O)OR⁷, —NR⁷C (O)R⁷, cycloalkyl, optionallysubstituted 5-6 membered heterocyclyl, optionally substitutedheteroarylalkylenyl, optionally substituted phenyl, lower alkylsubstituted with R¹, cyano, nitro, lower alkenyl and lower alkynyl,preferably halo, —OR⁷, —SR⁷, —CO₂R⁷, —CONR⁷R⁷, —COR⁷, —NR⁷R⁷, —SO₂NR⁷R⁷,—NR⁷C(O)OR⁷, —NR⁷C (O)R⁷, cyano, lower hydroxyalkyl, lower aminoalkyland nitro, more preferably halo, —OR⁷, —CONR⁷R⁷, —NR⁷R⁷, —SO₂NR⁷R⁷,—NR⁷C(O)OR⁷, —NR⁷C(O)R⁷, cyano, amino-C₁-C₂-alkyl, hydroxy-C₁-C₂-alkyl,and nitro, even more preferably chloro, fluoro, amino, hydroxy,hydroxymethyl, aminomethyl, nitro, methoxy and ethoxy;

[0040] wherein R⁴ is independently selected from C₂-C₄ alkylenyl, C₂-C₄alkenylenyl and C₂-C₄ alkynylenyl, where one of the CH₂ groups may besubstituted with an oxygen atom or an —NH—, preferably C₂₋₃-alkylenyl,where one of the CH₂ groups may be substituted with an oxygen atom or an—NH—;

[0041] wherein R⁵ is selected from H, lower alkyl, phenyl and loweraralkyl, preferably H or C₁₋₂-alkyl;

[0042] wherein R⁶ is selected from H or C₁₋₆-alkyl; and

[0043] wherein R⁷ is selected from H, lower alkyl, phenyl, 5-6 memberedheterocyclyl, C₃-C₆ cycloalkyl, and lower haloalkyl, preferably H,C₁₋₂-alkyl, phenyl, C₃-C₆ cycloalkyl and C₁₋₂-haloalkyl, more preferablyH, methyl, ethyl, cyclopropyl, cyclohexyl and trifluoromethyl;

[0044] and pharmaceutically acceptable salts thereof;

[0045] provided R³ is substituted with one or more radicals selectedfrom —OR⁷, —SR⁷, —CO₂R⁷, —CONR⁷R⁷, —COR⁷, —NR⁷R⁷, lower aminoalkyl,lower alkylaminoalkyl, —SO₂NR⁷R⁷, —NR⁷C(O)OR⁷, —NR⁷C(O)R⁷, cyano orlower hydroxyalkyl.

[0046] The invention also relates to compounds of Formula II

[0047] wherein each of A³ and A⁴ is independently C or N, provided atleast one of A³ and A⁴ is N; wherein n is 1-2; wherein R¹ is one or moresubstituents independently selected from H, chloro, fluoro, bromo,amino, hydroxy, methyl, ethyl, propyl, trifluoromethyl, methoxy, ethoxy,trifluoromethoxy, carboxymethyl, unsubstituted or substituted phenyl andunsubstituted or substituted heteroaryl selected from thienyl, furanyl,pyridyl, imidazolyl and pyrazolyl; wherein R² is selected from phenyl,isoquinolyl and quinolyl, where R² is unsubstituted or substituted withone or more substituents selected from chloro, fluoro, amino, hydroxy,cyclohexyl, phenylmethyl, morpholinylmethyl, methylpiperdinylmethyl,methylpiperazinylmethyl, ethyl, propyl, trifluoromethyl, phenyloxy,methoxy and ethoxy; and wherein R⁸ is one or more substituentsindependently selected from chloro, fluoro, methyl, cyano, amino,hydroxy, aminomethyl, hydroxymethyl, nitro, methoxy and ethoxy; andpharmaceutically acceptable salts thereof; provided R⁸ is one or moreradicals selected from amino, cyano, aminomethyl, hydroxymethyl,hydroxy, methoxy and ethoxy.

[0048] A class of compounds useful in treating cancer and angiogenesisis defined by Formula I′

[0049] wherein each of A¹ and A² is independently C or N;

[0050] wherein A¹-A² form part of a ring A selected from 5- or6-membered heteroaryl, preferably

[0051] I) 5-membered heteroaryl selected from thienyl, furanyl,pyrrolyl, thiazolyl, oxazolyl, imidazolyl, pyrazolyl, isoxazolyl,triazolyl and isothiazolyl, even more preferably 5-membered heteroarylselected from

[0052] II) preferably 6-membered heteroaryl selected from pyridyl,pyrazinyl, pyrimidinyl, pyridazinyl, and triazinyl, even more preferably6-membered heteroaryl selected from

[0053] specifically, pyridyl and pyrimidinyl, more specifically

[0054] wherein X is

[0055] preferably X is

[0056] wherein Z is oxygen or sulfur;

[0057] Y is selected from

[0058]  more preferably —NH—CH₂—;

[0059] wherein p is 0 to 2, preferably 2;

[0060] wherein R^(a) and R^(b) are independently selected from H, halo,cyano, —NHR⁶ and C₁₋₄-alkyl substituted with R¹, or wherein R^(a) andR^(b) together form C₃-C₆ cycloalkyl;

[0061] preferably H, halo, and C₁-₂-alkyl substituted with R¹, or

[0062] wherein R^(a) and R^(b) together form C₃-C₄ cycloalkyl, morepreferably H, chloro, fluoro and C₁-C₂-alkyl, even more preferably H;

[0063] wherein R^(z) is selected from C₂-C₆-alkylenyl, where one of theCH₂ groups may be replaced with an oxygen atom or an —NH— group; whereinone of the CH₂ groups may be substituted with one or two radicalsselected from halo, cyano, —NHR⁶ and C₁₋₄-alkyl substituted with R¹;

[0064] preferably C₂-C₃ alkylenyl, where one of the CH₂ groups may bereplaced with an oxygen atom or an —NH—, more preferably —(CH₂)₂—;

[0065] wherein R^(d) is optionally substituted cycloalkyl, preferablyC₃₋₆-cycloalkyl;

[0066] wherein R¹ is one or more substituents independently selectedfrom H, halo, —OR⁷, oxo, —SR⁷, —CO₂R⁷, —COR⁷, —CONR R⁷R⁷, —NR⁷R⁷,—SO₂NR⁷R⁷, —NR⁷C(O)OR⁷, —NR⁷C(O)R⁷, optionally substituted cycloalkyl,optionally substituted phenylalkyl, optionally substituted heterocyclyl,optionally substituted heterocyclylalkyl, optionally substituted phenyl,lower alkyl, cyano, lower hydroxyalkyl, lower carboxyalkyl, nitro, loweralkenyl, lower alkynyl, lower aminoalkyl, lower alkylaminoalkyl andlower haloalkyl,

[0067] preferably H, halo, —OR⁷, oxo, —SR⁷, —CO₂R⁷, —CONR⁷R⁷, —COR⁷,—NR⁷R⁷, —SO₂NR⁷R⁷, —NR⁷C(O)OR⁷, —NR⁷C(O)R⁷, optionally substitutedC₃₋₆-cycloalkyl, optionally substituted phenyl-C₁₋₄-alkyl, optionallysubstituted 4-6 membered heterocyclyl, optionally substituted phenyl,optionally substituted 4-6 membered heterocyclyl-C₁₋₄-alkyl, C₁₋₆-alkyl,cyano, C₁₋₄-hydroxyalkyl, C₁₋₄-carboxyalkyl, nitro, C₂₋₃-alkenyl,C₂₋₃-alkynyl and C₁₋₄-haloalkyl, more preferably H, halo, hydroxy,C₁₋₂-alkoxy, C₁₋₂-haloalkoxy, amino, C₁₋₂-alkylamino, optionallysubstituted 4-6 membered heterocyclyl-C₁₋₂-alkylamino, aminosulfonyl,C₃₋₆-cycloalkyl, optionally substituted 4-6 membered heterocyclyl,optionally substituted phenyl, C₁₋₄-alkyl, cyano, C₁₋₂-hydroxyalkyl,C₁₋₃-carboxyalkyl, nitro, C₂₋₃-alkenyl, C₂₋₃-alkynyl and C₁₋₂-haloalkyl,and even more preferably H, chloro, fluoro, bromo, hydroxy, methoxy,ethoxy, trifluoromethoxy, oxo, amino, dimethylamino, aminosulfonyl,carboxymethyl, cyclopropyl, optionally substituted phenyl, methyl,ethyl, propyl, cyano, hydroxymethyl, nitro, propenyl, propynyl,trifluoromethyl and unsubstituted or substituted heteroaryl selectedfrom thienyl, furanyl, pyridyl, imidazolyl and pyrazolyl;

[0068] wherein R² is selected from

[0069] a) substituted or unsubstituted 6-10 membered aryl, preferablyphenyl, naphthyl, benzodioxolyl, indanyl, indenyl andtetrahydronaphthyl, more preferably phenyl, indanyl, tetrahydronaphthyl,and naphthyl,

[0070] b) substituted or unsubstituted 5-6 membered heterocyclyl,preferably 5-6 membered heteroaryl, more preferably isoxazolyl,pyrazolyl, thiazolyl, thiadiazolyl, thienyl, pyridyl, pyrimidinyl,pyridazinyl, imidazolyl, oxazolyl, furyl and pyrrolyl,

[0071] c) substituted or unsubstituted 9-14 membered bicyclic ortricyclic heterocyclyl, preferably 9-10 membered bicyclic or 13-14membered tricyclic heterocyclyl, more preferably indazolyl, indolyl,isoindolyl, 2,3-dihydro-1H-indolyl, naphthyridinyl,2,1,3-benzothiadiazolyl, isoquinolyl, quinolyl, 1,2-dihydroquinolyl,1,2,3,4-tetrahydro-isoquinolyl,2,3,4,4a,9,9a-hexahydro-1H-3-aza-fluorenyl,5,6,7-trihydro-1,2,4-triazolo[3,4-a]isoquinolyl,3,4-dihydro-2H-benzo[1,4]oxazinyl, benzothienyl, tetrahydroquinolyl,benzofuryl, benzimidazolyl, benzoxazolyl, benzthiazolyl, benzodioxanyland quinazolinyl, even more preferably 9-10 membered bicyclic or 13-14membered tricyclic saturated or partially unsaturated heterocyclyl,specifically 1,2-dihydroquinolyl, 1,2,3,4-tetrahydro-isoquinolyl,1,2,3,4-tetrahydro-quinolyl, 2,3-dihydro-1H-indolyl,2,3,4,4a,9,9a-hexahydro-1H-3-aza-fluorenyl,5,6,7-trihydro-1,2,4-triazolo[3,4-a]isoquinolyl,3,4-dihydro-2H-benzo[1,4]oxazinyl, and benzo [1,4]dioxanyl;

[0072] d) cycloalkyl, preferably C₃₋₆-cycloalkyl, more preferablycyclohexyl, and

[0073] e) cycloalkenyl, wherein substituted R² is substituted with oneor more substituents independently selected from halo, —OR⁷, oxo, —SR⁷,—CO₂R⁷, —CONR⁷R⁷, —COR⁷, —NR⁷R⁷, —NH (C₁-C₄ alkylenylR⁹), —SO₂R⁷,—SO₂NR⁷R⁷, —NR⁷C(O)OR⁷, —NR⁷C(O)R⁷, —NR⁷C(O) NR⁷R⁷, optionallysubstituted cycloalkyl, optionally substituted heterocyclyl, optionallysubstituted phenyl, halosulfonyl, cyano, alkylaminoalkoxy,alkylaminoalkoxyalkoxy, nitro, lower alkyl substituted with R¹, loweralkenyl substituted with R¹, and lower alkynyl substituted with R¹,preferably halo, —OR⁷, oxo, —SR⁷, —SO₂R⁷, —CO₂R⁷, —CONR⁷R⁷, —COR⁷,—NR⁷R⁷, —NH (C₁-C₂-alkylenylR⁹), —(C₁-C₂-alkylenyl)NR⁷R⁷, —SO₂NR⁷R⁷,—NR⁷C(O)OR⁷, —NR⁷C(O)R⁷, C₁-C₆-alkylamino-C₁-C₆-alkoxy,C₁-C₆-alkylamino-C₁-C₆-alkoxy-C₁-C₆-alkoxy, halosulfonyl, optionallysubstituted 4-6 membered heterocyclylcarbonylalkyl,C₁₋₄-alkoxycarbonylamino-C₁₋₆-alkyl,

[0074] optionally substituted C₃₋₆-cycloalkyl, optionally substituted4-6 membered heterocyclyl, optionally substituted phenyl, optionallysubstituted phenyl-C₁₋₆-alkylenyl, optionally substituted 4-6 memberedheterocyclyl-C₁-C₆-alkylenyl, 4-6 memberedheterocyclyl-C₂-C₆-alkenylenyl, C₁₋₄-alkyl, cyano, C₁₋₄-hydroxyalkyl,nitro and C₁₋₄-haloalkyl, more preferably halo, C₁₋₄-alkyl, optionallysubstituted C₃₋₆-cycloalkyl, optionally substituted phenyl, optionallysubstituted phenyl-C₁-C₄-alkylenyl, C₁₋₂-haloalkoxy, optionallysubstituted phenyloxy, optionally substituted 4-6 memberedheterocyclyl-C₁-C₄-alkylenyl, optionally substituted 4-6 memberedheterocyclyl-C₂-C₄-alkenylenyl, optionally substituted 4-6 memberedheterocyclyl, optionally substituted 4-6 membered heterocyclyloxy,optionally substituted 4-6 membered heterocyclylsulfonyl, optionallysubstituted 4-6 membered heterocyclylamino, optionally substituted 4-6membered heterocyclylcarbonyl, optionally substituted 4-6 memberedheterocyclyl-C₁₋₄-alkylcarbonyl, C₁₋₂-haloalkyl, C₁₋₄-aminoalkyl, nitro,amino, hydroxy, cyano, aminosulfonyl, C₁₋₂-alkylsulfonyl, halosulfonyl,C₁₋₄-alkylcarbonyl, C₁₃-alkylamino-C₁₋₃-alkyl,C₁₋₃-alkylamino-C₁₋₃-alkoxy, C₁₋₃-alkylamino-C₁₋₃-alkoxy-C₁₋₃-alkoxy,C₁₋₄-alkoxycarbonyl, C₁₋₄-alkoxycarbonylamino-C₁₋₄-alkyl,C₁₋₄-hydroxyalkyl,

[0075] and C₁₋₄-alkoxy, even more preferably bromo, chloro, fluoro,iodo, nitro, amino, cyano, aminoethyl, Boc-aminoethyl, hydroxy,aminosulfonyl, 4-methylpiperazinylsulfonyl, cyclohexyl, phenyl,phenylmethyl, morpholinylmethyl, methylpiperazinylmethyl,morpholinylethyl, methylpiperazinylpropyl,1-(4-morpholinyl)-2,2-dimethylpropyl, piperidinylmethyl,morpholinylpropyl, methylpiperidinylmethyl, piperidinylethyl,piperidinylpropyl, pyrrolidinylpropyl, pyrrolidinylpropenyl,pyrrolidinylbutenyl, fluorosulfonyl, methylsulfonyl, methylcarbonyl,piperidinylmethylcarbonyl, methylpiperazinylcarbonylethyl,methoxycarbonyl, 3-ethoxycarbonyl-2-methyl-fur-5-yl, methylpiperazinyl,methylpiperidyl, 1-methyl-(1,2,3,6-tetrahydropyridyl), imidazolyl,morpholinyl, 4-trifluoromethyl-1-piperidinyl, hydroxybutyl, methyl,ethyl, propyl, isopropyl, butyl, tert-butyl, sec-butyl, trifluoromethyl,pentafluoroethyl, nonafluorobutyl, dimethylaminopropyl,1,1-di(trifluoromethyl)-1-hydroxymethyl, trifluoromethoxy,1,1-di(trifluoromethyl)-1-(piperidinylethoxy)methyl,1,1-di(trifluoromethyl)-1-(methoxyethoxyethoxy)methyl, 1-hydroxyethyl,2-hydroxyethyl, 1-aminoethyl, 2-aminoethyl, 1-(N-isopropylamino)ethyl,2-(N-isopropylamino) ethyl, dimethylaminoethoxy, 4-chlorophenoxy,phenyloxy, 1-methylpiperdin-4-yloxy, isopropoxy, methoxy and ethoxy;

[0076] wherein R³ is selected from unsubstituted or substituted aryl,preferably substituted phenyl,

[0077] wherein substituted R³ is substituted with one or moresubstituents independently selected from halo, —OR⁷, —SR⁷, —SO₂R⁷,—CO₂R⁷, —CONR⁷R⁷, —COR ⁷, —NR⁷R⁷, —SO₂NR⁷R⁷, —NR⁷C(O)OR⁷, —NR⁷C(O)R⁷,cycloalkyl, optionally substituted heterocyclyl, optionally substitutedphenyl, nitro, alkylaminoalkoxyalkoxy, cyano, alkylaminoalkoxy, loweralkyl substituted with R¹, lower alkenyl substituted with R¹, and loweralkynyl substituted with R¹;

[0078] preferably halo, —OR⁷, —SR⁷, —CO₂R⁷, —CONR⁷R⁷, —COR⁷, —NR⁷R⁷,—SO₂NR⁷R⁷, —NR⁷C(O)OR⁷, —NR⁷C(O)R⁷, C₃₋₆-cycloalkyl, optionallysubstituted 4-6 membered heterocyclyl, optionally substituted phenyl,C₁₋₄-alkyl, C₁₋₄-aminoalkyl, cyano, C₁₋₄-hydroxyalkyl, nitro andC₁₋₄-haloalkyl, more preferably halo, hydroxy, C₁₋₄-alkyl, C₁₋₂-alkoxy,optionally substituted 4-6 membered heterocyclyl-C₁₋₂-alkoxy, amino,C₁₋₂-alkylamino, aminosulfonyl, —NR⁷C(O)OR⁷, —NR⁷C(O)R⁷,C₃₋₆-cycloalkyl, optionally substituted 4-6 membered heterocyclyl,optionally substituted phenyl, nitro,C₁₋₂-alkylamino-C₁₋₂-alkoxy-C₁₋₂-alkoxy, cyano,C₁₋₂-alkylamino-C₁₋₂-alkoxy, C₁₋₂-alkylamino-C₁₋₂-alkyl,C₁₋₂-alkylamino-C₂₋₃-alkynyl, C₁₋₂-hydroxyalkyl, C₁₋₂-aminoalkyl,C₁₋₂-haloalkyl, optionally substituted 4-6 memberedheterocyclyl-C₂₋₃-alkenyl, and optionally substituted 4-6 memberedheterocyclyl-C₂₋₃-alkynyl, even more preferably chloro, fluoro, bromo,hydroxy, methoxy, ethoxy, amino, dimethylamino, diethylamino,1-methylpiperidinylmethoxy, aminosulfonyl, cyclohexyl,dimethylaminopropynyl, dimethylaminoethoxy,3-(4-morpholinyl)propyn-1-yl, dimethylaminoethoxyethoxy, optionallysubstituted piperidinyl, morpholinyl, optionally substitutedpiperazinyl, optionally substituted phenyl, methyl, ethyl, propyl,cyano, hydroxymethyl, aminomethyl, nitro and trifluoromethyl;

[0079] wherein R⁴ is independently selected from a direct bond,C₂₋₄-alkylenyl, C₂₋₄-alkenylenyl and C₂₋₄-alkynylenyl, where one of theCH₂ groups may be substituted with an oxygen atom or —NH—, wherein R⁴ isoptionally substituted with hydroxy, preferably a direct bond or R^(4a);

[0080] wherein R^(4a) is selected from C₂₋₄-alkylenyl where one of theCH₂ groups may be replaced with an oxygen atom or —NH—,

[0081] wherein R^(4a) is optionally substituted with hydroxy, preferablyethyl, butyl, and

[0082] wherein R⁵ is selected from H, lower alkyl, phenyl and loweraralkyl, preferably H, methyl or ethyl, more preferably H;

[0083] wherein R^(5a) is selected from H, lower alkyl, phenyl and loweraralkyl, preferably H, methyl or ethyl, more preferably H;

[0084] wherein R⁶ is selected from H or C₁₋₆-alkyl, preferably H or C₁₋₂alkyl;

[0085] wherein R⁷ is selected from H, lower alkyl, optionallysubstituted phenyl, optionally substituted heterocyclyl, optionallysubstituted C₃-C₆-cycloalkyl, optionally substituted phenyl-C₁₋₆-alkyl,optionally substituted heterocyclyl-C₁₋₆-alkyl, optionally substitutedC₃-C₆ cycloalkyl-C₁₋₆-alkyl, lower alkylaminoalkyl, and lower haloalkyl,preferably H, C₁₋₄-alkyl, optionally substituted phenyl, optionallysubstituted phenyl-C₁₋₄-alkyl, optionally substituted 4-6 memberedheterocyclyl, optionally substituted 4-6 memberedheterocyclyl-C₁₋₄-alkyl, optionally substituted C₃-C₆ cycloalkyl,C₁₋₂-alkylamino-C₁₋₄-alkyl and C₁₋₂-haloalkyl, more preferably H,methyl, phenyl, cyclopropyl, cyclohexyl, benzyl, morpholinylmethyl,4-methylpiperazinylmethyl, 4-methylpiperdinylmethyl,4-morpholinylmethyl, 4-morpholinylethyl,1-(4-morpholinyl)-2,2-dimethylpropyl, 1-piperdinylethyl,1-piperdinylpropyl, 1-pyrrolidinylpropyl and trifluoromethyl;

[0086] wherein R^(c) is selected from H, methyl and optionallysubstituted phenyl; and

[0087] wherein R^(e) and R^(f) are independently selected from H andC₁₋₂-haloalkyl, preferably —CF₃;

[0088] wherein R^(g) is selected from H, C₁₋₆-alkyl, optionallysubstituted phenyl-C₁₋₆-alkyl, optionally substituted 4-6 memberedheterocyclyl, optionally substituted 4-6 memberedheterocyclyl-C₁-C₆-alkyl, C₁₋₄-alkoxy-C₁₋₄-alkyl andC₁₋₄-alkoxy-C₁₋₄-alkoxy-C₁₋₄-alkyl, preferably H, C₁₋₃-alkyl, optionallysubstituted phenyl-C₁₋₃-alkyl, optionally substituted 4-6 memberedheterocyclyl-C₁-C₃-alkyl, C₁₋₃-alkoxy-C₁₋₃-alkyl andC₁₋₃-alkoxy-C₁₃-alkoxy-C₁₋₃-alkyl; and

[0089] wherein R⁹ is selected from H, optionally substituted phenyl,optionally substituted 4-6 membered heterocyclyl and C₃-C₆ cycloalkyl;

[0090] provided R² is not 3-trifluoromethylphenyl when A is pyridyl,when X is —C(O)NH—, when Y is —NH—CH₂—, when R¹ is H and R³ is3-(N-methylamino-carbonyl)phenyl, 4-hydroxyphenyl, 3-hydroxyphenyl orphenyl;

[0091] further provided R² is not substituted with —SO₂NR⁷R⁷ when Y is—NHSO₂—;

[0092] further provided R² is not 3-trifluoromethylphenyl when A ispyridyl, when X is —C(O)NH—, when Y is —N(benzyl)-CH₂—, when R¹ is H andwhen R³ is phenyl;

[0093] further provided R² is not cyclohexyl when A is pyridyl, when Xis —C(O)NH—, when Y is —NH—CH₂—, when R¹ is H and when R³ is2-methoxyphenyl or 3-methoxyphenyl;

[0094] further provided R¹ is not 2-hydroxymethylpyrrol-5-yl when A ispyridyl;

[0095] further provided R¹ is not 4-(methoxyaminocarbonylamino)phenylwhen A is thienyl;

[0096] further provided R¹ is not 2-pyridylmethoxy when A is pyrimidyl,when X is —C(O)NH—, and when Y is —NH—CH₂—;

[0097] further provided R¹ is not 4-methylpiperidyl when A is pyrimidyl,when X is —C(O)NH—, when Y is —NH—CH₂—, and when R³ is3-chloro-4-methoxyphenyl;

[0098] further provided R¹ is not bromo when A is pyrimidyl, when X is—C(O)NH—CH₂—, when Y is —NH—CH₂—, and when R³ is3-chloro-4-methoxyphenyl;

[0099] further provided R² is not 2-chloro-3-pyridyl when A is pyridyl;and

[0100] further provided R² is not 2-methoxyphenyl when A is pyridyl,when X is —C(O)NH—, when Y is —NH—CH₂—, when R¹ is H and R³ is phenyl.

[0101] The invention also relates to compounds of Formula II′

[0102] wherein each of A³ and A⁴ is independently CH or N, provided atleast one of A³ and A⁴ is N;

[0103] wherein n is 1-2;

[0104] wherein R¹ is one or more substituents independently selectedfrom H, chloro, fluoro, bromo, hydroxy, methoxy, ethoxy,trifluoromethoxy, oxo, amino, dimethylamino, aminosulfonyl,carboxymethyl, cyclopropyl, optionally substituted phenyl, methyl,ethyl, propyl, cyano, hydroxymethyl, nitro, propenyl, propynyl,morpholinylethylamino, trifluoromethyl and unsubstituted or substitutedheteroaryl selected from thienyl, furanyl, pyridyl, imidazolyl andpyrazolyl;

[0105] wherein R² is a substituted or unsubstituted ring selected fromphenyl, tetrahydronaphthyl, indanyl, benzodioxolyl, indenyl, naphthyl,isoxazolyl, pyrazolyl, thiazolyl, thiadiazolyl, thienyl, pyridyl,pyrimidinyl, pyridazinyl, 1,2-dihydroquinolyl,1,2,3,4-tetrahydro-isoquinolyl, 1,2,3,4-tetrahydro-quinolyl,isoquinolyl, quinolyl, indolyl, isoindolyl, 2,3-dihydro-1H-indolyl,naphthyridinyl, quinozalinyl, 2,3,4, 4a, 9,9a-hexahydro-1H-3-aza-fluorenyl,5,6,7-trihydro-1,2,4-triazolo[3,4-a]isoquinolyl, indazolyl,2,1,3-benzothiadiazolyl, 3,4-dihydro-2H-benzo[1,4]oxazinyl,benzodioxanyl, benzothienyl, benzofuryl, benzimidazolyl, benzoxazolyland benzthiazolyl;

[0106] wherein substituted R² is substituted with one or moresubstituents independently selected from bromo, chloro, fluoro, iodo,nitro, amino, cyano, aminoethyl, Boc-aminoethyl, hydroxy, oxo,aminosulfonyl, 4-methylpiperazinylsulfonyl, cyclohexyl, phenyl,phenylmethyl, morpholinylmethyl, 1-methylpiperazin-4-ylmethyl,1-methylpiperazin-4-ylpropyl, morpholinylpropyl, piperidin-1-ylmethyl,1-methylpiperidin-4-ylmethyl, 2-methyl-2-(1-methylpiperidin-4-yl)ethyl,morpholinylethyl, 1-(4-morpholinyl)-2,2-dimethylpropyl,piperidin-4-ylethyl, 1-Boc-piperidin-4-ylethyl, piperidin-1-ylethyl,1-Boc-piperidin-4-ylethyl, piperidin-4-ylmethyl,1-Boc-piperidin-4-ylmethyl, piperidin-4-ylpropyl,1-Boc-piperidin-4-ylpropyl, piperidin-1-ylpropyl, pyrrolidin-1-ylpropyl,pyrrolidin-2-ylpropyl, 1-Boc-pyrrolidin-2-ylpropyl,pyrrolidin-1-ylmethyl, pyrrolidin-2-ylmethyl,1-Boc-pyrrolidin-2-ylmethyl, pyrrolidinylpropenyl, pyrrolidinylbutenyl,fluorosulfonyl, methylsulfonyl, methylcarbonyl, Boc,piperidin-1-ylmethylcarbonyl, 4-methylpiperazin-1-ylcarbonylethyl,methoxycarbonyl, aminomethylcarbonyl, dimethylaminomethylcarbonyl,3-ethoxycarbonyl-2-methyl-fur-5-yl, 4-methylpiperazin-1-yl,4-methyl-1-piperidyl, 1-Boc-4-piperidyl, piperidin-4-yl,1-methylpiperidin-4-yl, 1-methyl-(1,2,3,6-tetrahydropyridyl),imidazolyl, morpholinyl, 4-trifluoromethyl-1-piperidinyl, hydroxybutyl,methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, sec-butyl,trifluoromethyl, pentafluoroethyl, nonafluorobutyl, dimethylaminopropyl,1,1-di(trifluoromethyl)-1-hydroxymethyl,1,1-di(trifluoromethyl)-1-(piperidinylethoxy)methyl,1,1-di(trifluoromethyl)-1-(methoxyethoxyethoxy)methyl, 1-hydroxyethyl,2-hydroxyethyl, trifluoromethoxy, 1-aminoethyl, 2-aminoethyl,1-(N-isopropylamino)ethyl, 2-(N-isopropylamino)ethyl,dimethylaminoethoxy, 4-chlorophenoxy, phenyloxy, azetidin-3-ylmethoxy,1-Boc-azetidin-3-ylmethoxy, pyrrol-2-ylmethoxy,1-Boc-pyrrol-2-ylmethoxy, pyrrol-1-ylmethoxy,1-methyl-pyrrol-2-ylmethoxy, 1-isopropyl-pyrrol-2-ylmethoxy,1-Boc-piperdin-4-ylmethoxy, piperdin-4-ylmethoxy,1-methylpiperdin-4-yloxy, isopropoxy, methoxy and ethoxy; and

[0107] wherein R⁸ is one or more substituents independently selectedfrom H, chloro, fluoro, bromo, hydroxy, methoxy, ethoxy, —O—CH₂—O—,trifluoromethoxy, 1-methylpiperidinylmethoxy, dimethylaminoethoxy,amino, dimethylamino, dimethylaminopropyl, diethylamino, aminosulfonyl,cyclohexyl, dimethylaminopropynyl, 3-(4-morpholinyl)propyn-1-yl,dimethylaminoethoxyethoxy, 3-(4-morpholinyl)propylamino, optionallysubstituted piperidinyl, morpholinyl, optionally substitutedpiperazinyl, optionally substituted phenyl, methyl, ethyl, propyl,cyano, hydroxymethyl, aminomethyl, nitro and trifluoromethyl;

[0108] provided R² is not 3-trifluoromethylphenyl when A³ is N, when A⁴is CH, when n is 1, when R¹ is H and R⁸ is 4-hydroxy, 3-hydroxy or H;further provided R² is not 2-chloro-3-pyridyl when A³ is N, when A⁴ isCH, when n is 1, when R¹ is H and R⁸ is H or 4-methoxy; and furtherprovided R² is not 2-methoxyphenyl when A³ is N, when A⁴ is CH, when nis 1, when R¹ is H and R⁸ is H.

[0109] The invention also relates to compounds of Formula III

[0110] wherein R¹ is one or more substituents independently selectedfrom

[0111] H,

[0112] halo,

[0113] hydroxy,

[0114] amino,

[0115] C₁₋₆-alkyl,

[0116] C₁₋₆-haloalkyl,

[0117] C₁₋₆-alkoxy,

[0118] C₁₋₂-alkylamino,

[0119] aminosulfonyl,

[0120] C₃₋₆-cycloalkyl,

[0121] cyano,

[0122] oxo,

[0123] C₁₋₂-hydroxyalkyl,

[0124] nitro,

[0125] C₂₋₃-alkenyl,

[0126] C₂₋₃-alkynyl,

[0127] C₁₋₆-haloalkoxy,

[0128] C₁₋₆-carboxyalkyl,

[0129] 5-6-membered heterocyclyl-C₁₋₆-alkylamino,

[0130] unsubstituted or substituted phenyl and

[0131] unsubstituted or substituted 4-6 membered heterocyclyl,

[0132] preferably H, chloro, fluoro, bromo, amino, hydroxy, methyl,ethyl, propyl, oxo, dimethylamino, aminosulfonyl, cyclopropyl, cyano,hydroxymethyl, nitro, propenyl, trifluoromethyl, methoxy, ethoxy,trifluoromethoxy, carboxymethyl, morpholinylethylamino, propynyl,unsubstituted or substituted phenyl and unsubstituted or substitutedheteroaryl selected from thienyl, furanyl, pyridyl, imidazolyl, andpyrazolyl, more preferably H, chloro or fluoro;

[0133] wherein R² is selected from unsubstituted or substituted phenyl,and 9-10 membered bicyclic and 13-14 membered tricyclic unsaturated orpartially unsaturated heterocyclyl, preferably phenyl,1,2-dihydroquinolyl, 1,2,3,4-tetrahydro-isoquinolyl,1,2,3,4-tetrahydro-quinolyl, 2,3-dihydro-1H-indolyl,2,3,4,4a,9,9a-hexahydro-1H-3-aza-fluorenyl,5,6,7-trihydro-1,2,4-triazolo[3,4-a]isoquinolyl,3,4-dihydro-2H-benzo[1,4]oxazinyl, and benzo[l,4]dioxanyl, morepreferably phenyl, 1,2,3,4-tetrahydro-isoquinolyl,1,2,3,4-tetrahydro-quinolyl, 2,3-dihydro-1H-indolyl and3,4-dihydro-2H-benzo[1,4]oxazinyl;

[0134] wherein substituted R² is substituted with one or moresubstituents selected from halo, C₁₋₆-alkyl, optionally substitutedC₃₋₆-cycloalkyl, optionally substituted phenyl, optionally substitutedphenyl-C₁-C₄-alkylenyl, C₁₋₂-haloalkoxy, optionally substitutedphenyloxy, optionally substituted 4-6 membered heterocyclyl-C₁-C₄-alkyl,optionally substituted 4-6 membered heterocyclyl-C₂-C₄-alkenyl,optionally substituted 4-6 membered heterocyclyl, optionally substituted4-6 membered heterocyclyloxy, optionally substituted 4-6 memberedheterocyclyl-C₁-C₄-alkoxy, optionally substituted 4-6 memberedheterocyclylsulfonyl, optionally substituted 4-6 memberedheterocyclylamino, optionally substituted 4-6 memberedheterocyclylcarbonyl, optionally substituted 5-6 memberedheterocyclylcarbonyl-c₁₋₄-alkyl, optionally substituted 4-6 memberedheterocyclyl-C₁₋₄-alkylcarbonyl, C₁₋₂-haloalkyl, C₁₋₄-aminoalkyl, nitro,amino, hydroxy, cyano, aminosulfonyl, C₁₋₂-alkylsulfonyl, halosulfonyl,C₁₋₄-alkylcarbonyl, C₁₋₃-alkylamino-C₁₋₃-alkyl,C₁₋₃-alkylamino-C₁₋₃-alkoxy, C₁₋₃-alkylamino-C₁₋₃-alkoxy-C₁₋₃-alkoxy,C₁₋₄-alkoxycarbonyl, C₁₋₄-alkoxycarbonylamino-C₁₋₄-alkyl,C₁₋₄-hydroxyalkyl,

[0135] and C₁₋₄-alkoxy, preferably bromo, chloro, fluoro, iodo, nitro,amino, cyano, aminoethyl, Boc-aminoethyl, hydroxy, oxo, aminosulfonyl,4-methylpiperazinylsulfonyl, cyclohexyl, phenyl, phenylmethyl,morpholinylmethyl, 1-methylpiperazin-4-ylmethyl,1-methylpiperazin-4-ylpropyl, morpholinylpropyl, piperidin-1-ylmethyl,1-methylpiperidin-4-ylmethyl, 2-methyl-2-(1-methylpiperidin-4-yl)ethyl,morpholinylethyl, 1-(4-morpholinyl)-2,2-dimethylpropyl,piperidin-4-ylethyl, 1-Boc-piperidin-4-ylethyl, piperidin-1-ylethyl,1-Boc-piperidin-4-ylethyl, piperidin-4-ylmethyl,1-Boc-piperidin-4-ylmethyl, piperidin-4-ylpropyl,1-Boc-piperidin-4-ylpropyl, piperidin-1-ylpropyl, pyrrolidin-1-ylpropyl,pyrrolidin-2-ylpropyl, 1-Boc-pyrrolidin-2-ylpropyl,pyrrolidin-1-ylmethyl, pyrrolidin-2-ylmethyl,1-Boc-pyrrolidin-2-ylmethyl, pyrrolidinylpropenyl, pyrrolidinylbutenyl,fluorosulfonyl, methylsulfonyl, methylcarbonyl, Boc,piperidin-1-ylmethylcarbonyl, 4-methylpiperazin-1-ylcarbonylethyl,methoxycarbonyl, aminomethylcarbonyl, dimethylaminomethylcarbonyl,3-ethoxycarbonyl-2-methyl-fur-5-yl, 4-methylpiperazin-1-yl,4-methyl-1-piperidyl, 1-Boc-4-piperidyl, piperidin-4-yl,1-methylpiperidin-4-yl, 1-methyl-(1,2,3,6-tetrahydropyridyl),imidazolyl, morpholinyl, 4-trifluoromethyl-1-piperidinyl, hydroxybutyl,methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, sec-butyl,trifluoromethyl, pentafluoroethyl, nonafluorobutyl, dimethylaminopropyl,1,1-di(trifluoromethyl)-1-hydroxymethyl,1,1-di(trifluoromethyl)-1-(piperidinylethoxy)methyl,1,1-di(trifluoromethyl)-1-(methoxyethoxyethoxy)methyl, 1-hydroxyethyl,2-hydroxyethyl, trifluoromethoxy, 1-aminoethyl, 2-aminoethyl,1-(N-isopropylamino)ethyl, 2-(N-isopropylamino)ethyl,dimethylaminoethoxy, 4-chlorophenoxy, phenyloxy, azetidin-3-ylmethoxy,1-Boc-azetidin-3-ylmethoxy, pyrrol-2-ylmethoxy,1-Boc-pyrrol-2-ylmethoxy, pyrrol-1-ylmethoxy,1-methyl-pyrrol-2-ylmethoxy, 1-isopropyl-pyrrol-2-ylmethoxy,1-Boc-piperdin-4-ylmethoxy, piperdin-4-ylmethoxy,1-methylpiperdin-4-yloxy, isopropoxy, methoxy and ethoxy, morepreferably bromo, chloro, fluoro, morpholinylmethyl,1-methylpiperazin-4-ylmethyl, 1-methylpiperazin-4-ylpropyl,morpholinylpropyl, piperidin-1-ylmethyl, 1-methylpiperidin-4-ylmethyl,2-methyl-2-(1-methylpiperidin-4-yl)ethyl, morpholinylethyl,1-(4-morpholinyl)-2,2-dimethylpropyl, piperidin-4-ylethyl,1-Boc-piperidin-4-ylethyl, piperidin-1-ylethyl,1-Boc-piperidin-4-ylethyl, piperidin-4-ylmethyl,1-Boc-piperidin-4-ylmethyl, piperidin-4-ylpropyl,1-Boc-piperidin-4-ylpropyl, piperidin-1-ylpropyl, pyrrolidin-1-ylpropyl,pyrrolidin-2-ylpropyl, 1-Boc-pyrrolidin-2-ylpropyl,pyrrolidin-1-ylmethyl, pyrrolidin-2-ylmethyl,1-Boc-pyrrolidin-2-ylmethyl, 4-methylpiperazin-1-yl,4-methyl-1-piperidyl, 1-Boc-4-piperidyl, piperidin-4-yl,1-methyl-(1,2,3,6-tetrahydropyridyl), 1-methylpiperidin-4-yl,dimethylaminomethylcarbonyl, aminomethylcarbonyl, methylcarbonyl,methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, sec-butyl,trifluoromethyl, pentafluoroethyl, dimethylaminopropyl,dimethylaminoethoxy, 4-chlorophenoxy, phenyloxy, azetidin-3-ylmethoxy,1-Boc-azetidin-3-ylmethoxy, pyrrol-1-ylethoxy,1-methyl-pyrrol-2-ylmethoxy, pyrrol-2-ylmethoxy,1-Boc-pyrrol-2-ylmethoxy, 1-Boc-piperdin-4-ylmethoxy,piperdin-4-ylmethoxy, and 1-methylpiperdin-4-yloxy,

[0136] particularly when R² is phenyl, it has a substituent selectedfrom optionally substituted 4-6 membered heterocyclyl-C₁-C₄-alkyl,optionally substituted 4-6 membered heterocyclyl-C₂-C₄-alkenyl,optionally substituted 4-6 membered heterocyclyl, optionally substituted4-6 membered heterocyclyloxy, optionally substituted 4-6 memberedheterocyclyl-C₁-C₄-alkoxy, optionally substituted 4-6 memberedheterocyclylsulfonyl, optionally substituted 4-6 memberedheterocyclylamino, optionally substituted 4-6 memberedheterocyclylcarbonyl, optionally substituted 4-6 memberedheterocyclylcarbonyl-C₁₋₄-alkyl, optionally substituted 4-6 memberedheterocyclyl-C₁₋₄-alkylcarbonyl;

[0137] wherein R⁷ is selected from H, C₁₋₃-alkyl, optionally substitutedphenyl-C₁₋₃-alkyl, 4-6 membered heterocyclyl, and optionally substituted4-6 membered heterocyclyl-C₁-C₃-alkyl;

[0138] wherein R^(e) and R^(f) are independently selected from H andC₁₋₂-haloalkyl, preferably —CF₃;

[0139] wherein R^(g) is selected from H, C₁₋₃-alkyl, optionallysubstituted phenyl-C₁₋₃-alkyl, 4-6 membered heterocyclyl, and optionallysubstituted 4-6 membered heterocyclyl-C₁-C₃-alkyl,C₁₋₃-alkoxy-C₁₋₂-alkyl and C₁₋₃-alkoxy-C₁₋₃-alkoxy-C₁₋₃-alkyl; and

[0140] where R⁸ is one or more substituents selected from H, halo,amino, hydroxy, C₁₋₆-alkyl, C₁₋₆-haloalkyl, C₁₋₆-alkoxy,C₁₋₆-haloalkoxy, C₁₋₆-aminoalkyl, C₁₋₆-hydroxyalkyl, optionallysubstituted phenyl, optionally substituted heterocyclyl, optionallysubstituted heterocyclyl-C₁₋₆-alkoxy, aminosulfonyl, C₃₋₆-cycloalkyl,C₁₋₆-alkylamino, C₁₋₆-alkylamino-C₁₋₆-alkyl, optionally substitutedheterocyclyl-C₁₋₆-alkylamino, optionally substitutedheterocyclyl-C₁₋₆-alkyl, C₁₋₆-alkylamino-C₂₋₄-alkynyl,C₁₋₆-alkylamino-C₁₋₆-alkoxy, C₁₋₆-alkylamino-C₁₋₆-alkoxy-C₁₋₆-alkoxy,and optionally substituted heterocyclyl-C₂₋₄-alkynyl, preferably H,chloro, fluoro, bromo, hydroxy, methoxy, ethoxy, —O—CH₂—O—,trifluoromethoxy, 1-methylpiperidinylmethoxy, dimethylaminoethoxy,amino, dimethylamino, dimethylaminopropyl, diethylamino, aminosulfonyl,cyclohexyl, dimethylaminopropynyl, 3-(4-morpholinyl)propyn-1-yl,dimethylaminoethoxyethoxy, 3-(4-morpholinyl)propylamino, optionallysubstituted piperidinyl, morpholinyl, optionally substitutedpiperazinyl, optionally substituted phenyl, methyl, ethyl, propyl,cyano, hydroxymethyl, aminomethyl and trifluoromethyl, more preferablyH, chloro, fluoro, bromo, cyano, methoxy, —O—CH₂—O—, amino,trifluoromethyl, trifluoromethoxy, 3-(4-morpholinyl)propyn-1-yl,dimethylaminopropyl, and 3-(4-morpholinyl)propylamino, particularly4-fluoro;

[0141] provided R² is not 3-trifluoromethylphenyl when R¹ is H and R⁸ is4-hydroxy, 3-hydroxy or H; and further provided R² is not2-methoxyphenyl when R¹ is H and R⁸ is H.

[0142] The invention also relates to compounds of Formula IV

[0143] wherein R² is selected from unsubstituted or substituted phenyl,and 9-10 membered bicyclic and 11-14 membered tricyclic unsaturated orpartially unsaturated heterocyclyl, preferably phenyl,1,2-dihydroquinolyl, 1,2,3,4-tetrahydro-isoquinolyl,1′,2′-dihydro-spiro[cyclopropane-1,3′-[3H]indol]-6′-yl, isoquinolyl,quinolyl, indolyl, isoindolyl, 2,3-dihydro-1H-indolyl, naphthyridinyl,1,2,3,4-tetrahydro-[1,8]naphthyridinyl, quinozalinyl,benzo[d]isothiazolyl, 3,4-dihydro-quinazolinyl,3,4-dihydro-2H-benzo[1,4]oxazinyl,2,3,4,4a,9,9a-hexahydro-1H-3-aza-fluorenyl,5,6,7-trihydro-1,2,4-triazolo[3,4-a]isoquinolyl, tetrahydroquinolinyl,indazolyl, 2,1,3-benzothiadiazolyl, benzodioxanyl, benzothienyl,benzofuryl, benzimidazolyl, dihydro-benzimidazolyl, benzoxazolyl andbenzthiazolyl, more preferably4,4-dimethyl-1,2,3,4-tetrahydro-1H-isoquinolinyl optionally substitutedwith Boc, 4,4-dimethyl-1,2,3,4-tetrahydro-quinolyl optionallysubstituted with one or more substituents selected from Boc and oxo,3,3-dimethyl-2,3-dihydro-1H-indolyl optionally substituted with one ormore substituents selected from methylsulfonyl,1-Boc-piperidin-4-ylmethyl, piperidin-4-ylmethyl, 1-Boc-piperidin-4-yl,piperidin-4-yl, 1-methyl-piperidin-4-ylmethyl, 1-methyl-piperidin-4-yl,pyrrolidin-1-yl-carbonyl, dimethylaminomethylcarbonyl,aminomethylcarbonyl, methylcarbonyl, pyrrolidin-2-ylmethyl, and1-Boc-pyrrolidin-2-ylmethyl, and 3,4-dihydro-2H-benzo[1,4]oxazinyloptionally substituted with one or more substituents selected frommethyl, and methylcarbonyl; and

[0144] particularly 3,3-dimethyl-2,3-dihydro-1H-indolyl optionallysubstituted with a substituent selected from pyrrolidin-1-yl-carbonyl,methylcarbonyl, and methylsulfonyl, and4,4-dimethyl-1,2,3,4-tetrahydro-1H-isoquinolinyl;

[0145] wherein substituted R² is substituted with one or moresubstituents selected from halo, C₁₋₆-alkyl, optionally substitutedC₃₋₆-cycloalkyl, optionally substituted phenyl, optionally substitutedphenyl-C₁-C₄-alkylenyl, C₁₋₂-haloalkoxy, optionally substitutedphenyloxy, optionally substituted 4-6 membered heterocyclyl-C₁-C₆-alkyl,optionally substituted 4-6 membered heterocyclyl-C₂-C₄-alkenyl,optionally substituted 4-6 membered heterocyclyl, optionally substituted4-6 membered heterocyclyloxy, optionally substituted 4-6 memberedheterocyclyl-C₁₋₄-alkoxy, optionally substituted 4-6 memberedheterocyclylsulfonyl, optionally substituted 4-6 memberedheterocyclylamino, optionally substituted 4-6 memberedheterocyclylcarbonyl, optionally substituted 4-6 memberedheterocyclyl-C₁₋₄-alkylcarbonyl, optionally substituted 4-6 memberedheterocyclylcarbonyl-C₁₋₄-alkyl, optionally substituted 4-6 memberedheterocyclyl-C₁₋₄-alkylcarbonylamino, optionally substituted 4-6membered he-terocyclyl-oxycarbonylamino, C₁₋₂-haloalkyl,C₁₋₄-aminoalkyl, nitro, amino, C₁₋₃-alkylsulfonylamino, hydroxy, cyano,aminosulfonyl, C₁₋₂-alkylsulfonyl, halosulfonyl, C,₄-alkylcarbonyl,amino-C₁₋₄-alkylcarbonyl, C₁₋₃-alkylamino-C₁₋₄-alkylcarbonyl,C₁₋₃-alkylamino-C₁₋₄-alkylcarbonylamino, C₁₋₄-alkoxycarbonyl-C₁₋₄-alkyl,C₁₋₃-alkylamino-C₁₋₃-alkyl, C₁₋₃-alkylamino-C₁₋₃-alkoxy,C₁₋₃-alkylamino-C₁₋₃-alkoxy-C₁₋₃-alkoxy, C₁₋₄-alkoxycarbonyl,C₁₋₄-alkoxycarbonylamino-C₁₋₄-alkyl,C₁₋₃-alkylsulfonylamino-C₁₋₃-alkoxy, C₁₋₄-hydroxyalkyl,

[0146] and C₁₋₄-alkoxy, preferably bromo, chloro, fluoro, iodo, nitro,amino, cyano, Boc-aminoethyl, hydroxy, oxo, fluorosulfonyl,methylsulfonyl, aminosulfonyl, 4-methylpiperazinylsulfonyl, cyclohexyl,phenyl, phenylmethyl, 4-pyridylmethyl, 4-morpholinylmethyl,1-methylpiperazin-4-ylmethyl, 1-methylpiperazin-4-ylpropyl,morpholinylpropyl, piperidin-1-ylmethyl, 1-methylpiperidin-4-ylmethyl,2-methyl-2-(1-methylpiperidin-4-yl)ethyl,2-methyl-2-(4-pyrimidinyl)ethyl,2-methyl-2-(5-methyloxadiazol-2-yl)ethyl,2-methyl-2-(pyrazol-5-yl)ethyl,2-methyl-2-(1-ethoxycarbonyl-1,2,3,6-tetrahydropyridin-4-yl)ethyl,morpholinylethyl, 1-(4-morpholinyl)-2,2-dimethylpropyl,1-(4-morpholinyl)-2,2-dimethylethyl, piperidin-4-ylethyl,1-Boc-piperidin-4-ylethyl, piperidin-1-ylethyl,1-Boc-piperidin-4-ylethyl, piperidin-4-ylmethyl,1-Boc-piperidin-4-ylmethyl, piperidin-4-ylpropyl,1-Boc-piperidin-4-ylpropyl, piperidin-1-ylpropyl, pyrrolidin-1-ylpropyl,pyrrolidin-2-ylpropyl, 1-Boc-pyrrolidin-2-ylpropyl,1-(pyrrolidin-1-yl)-2-methylpropyl, pyrrolidin-1-ylmethyl,pyrrolidin-2-ylmethyl, 1-Boc-pyrrolidin-2-ylmethyl,2-methyl-2-(pyrrolidin-1-yl)ethyl, pyrrolidinylpropenyl,pyrrolidinylbutenyl, methylcarbonyl, Boc, piperidin-1-ylmethylcarbonyl,pyrrolidin-1-yl-carbonyl, pyrrolidin-2-yl-carbonyl, 4-pyridylcarbonyl,4-methylpiperazin-1-ylcarbonylethyl, CH₃O—C(═O)—CH₂—, methoxycarbonyl,aminomethylcarbonyl, dimethylaminomethylcarbonyl, methylsulfonylamino,dimethylaminomethylcarbonylamino, 1-pyrrolidinyl-CH₂—C(═O)—NH—,4-morpholinyl-CH₂—C(═O)—NH—, 3-tetrahydrofuryl-O—C(═O)—NH—,cyclohexyl-N(CH₃)—, (4-pyrimidinyl)amino,(2-methylthio-4-pyrimidinyl)amino, 3-ethoxycarbonyl-2-methyl-fur-5-yl,4-methylpiperazin-1-yl, 4-methyl-1-piperidyl, 1-Boc-4-piperidyl,piperidin-4-yl, 1-methylpiperidin-4-yl,1-methyl-(1,2,3,6-tetrahydropyridyl), imidazolyl, morpholinyl,4-trifluoromethyl-1-piperidinyl, hydroxybutyl, methyl, ethyl, propyl,isopropyl, butyl, tert-butyl, sec-butyl, trifluoromethyl,pentafluoroethyl, nonafluorobutyl, dimethylaminopropyl,1,1-di(trifluoromethyl)-1-hydroxymethyl,1,1-di(trifluoromethyl)-1-(piperidinylethoxy)methyl,1,1-di(trifluoromethyl)-1-(pyrrolidin-2-ylmethoxy)methyl,1,1-di(trifluoromethyl)-1-(methoxyethoxyethoxy)methyl, 1-hydroxyethyl,2-hydroxyethyl, trifluoromethoxy, 1-aminoethyl, 2-aminoethyl,1-(N-isopropylamino)ethyl, 2-(N-isopropylamino)ethyl,3-tetrahydrofuryloxy, dimethylaminoethoxy, 4-chlorophenoxy, phenyloxy,azetidin-3-ylmethoxy, 1-Boc-azetidin-3-ylmethoxy,3-tetrahydrofurylmethoxy, pyrrolidin-2-ylmethoxy,1-methylcarbonyl-pyrrolidin-2-ylmethoxy, 1-Boc-pyrrolidin-2-ylmethoxy,pyrrolidin-1-ylmethoxy, 1-methyl-pyrrolidin-2-ylmethoxy,1-isopropyl-pyrrolidin-2-ylmethoxy, 1-Boc-piperdin-4-ylmethoxy,(1-pyrrolidinyl)ethoxy, piperdin-4-ylmethoxy, piperdin-3-ylmethoxy,1-methylpiperdin-4-yloxy, methylsulfonylaminoethoxy, isopropoxy, methoxyand ethoxy, more preferably bromo, chloro, fluoro, morpholinylmethyl,1-methylpiperazin-4-ylmethyl, 1-methylpiperazin-4-ylpropyl,morpholinylpropyl, piperidin-1-ylmethyl, 1-methylpiperidin-4-ylmethyl,2-methyl-2-(l-methylpiperidin-4-yl)ethyl, morpholinylethyl,1-(4-morpholinyl)-2,2-dimethylpropyl, piperidin-4-ylethyl,1-Boc-piperidin-4-ylethyl, piperidin-1-ylethyl,1-Boc-piperidin-4-ylethyl, piperidin-4-ylmethyl,1-Boc-piperidin-4-ylmethyl, piperidin-4-ylpropyl,1-Boc-piperidin-4-ylpropyl, piperidin-1-ylpropyl, pyrrolidin-1-ylpropyl,pyrrolidin-2-ylpropyl, 1-Boc-pyrrolidin-2-ylpropyl,pyrrolidin-1-ylmethyl, pyrrolidin-2-ylmethyl,1-Boc-pyrrolidin-2-ylmethyl, 4-methylpiperazin-1-yl,4-methyl-1-piperidyl, 1-Boc-4-piperidyl, piperidin-4-yl,1-methyl-(1,2,3,6-tetrahydropyridyl), 1-methyl-piperidin-4-yl,dimethylaminomethylcarbonyl, aminomethylcarbonyl, methylcarbonyl,methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, sec-butyl,trifluoromethyl, pentafluoroethyl, dimethylaminopropyl,dimethylaminoethoxy, 4-chlorophenoxy, phenyloxy, azetidin-3-ylmethoxy,1-Boc-azetidin-3-ylmethoxy, pyrrol-1-ylethoxy,1-methyl-pyrrol-2-ylmethoxy, pyrrol-2-ylmethoxy,1-Boc-pyrrol-2-ylmethoxy, 1-Boc-piperdin-4-ylmethoxy,piperdin-4-ylmethoxy, and 1-methylpiperdin-4-yloxy, particularly when R²is phenyl, it has a substituent selected from chloro, tert-butyl,azetidin-3-ylmethoxy, 1-Boc-azetidin-3-ylmethoxy,dimethylaminomethylcarbonylamino,1,1-di(trifluoromethyl)-1-(pyrrolidin-2-ylmethoxy)methyl,trifluoromethyl, 2-methyl-2-(morpholin-4-yl)ethyl,2-methyl-2-(pyrrolidin-1-yl)ethyl,2-methyl-2-(5-methyloxadiazol-2-yl)ethyl, methylsulfonylamino,1-methyl-pyrrolidin-2-ylmethoxy,and isopropyl;

[0147] more particularly 3-trifluorophenyl meta-substituted with asubstituent selected from azetidin-3-ylmethoxy,1-Boc-azetidin-3-ylmethoxy, methylsulfonylamino and1-methyl-pyrrolidin-2-ylmethoxy;

[0148] wherein R^(e) and R^(f) are independently selected from H andC₁₋₂-haloalkyl, preferably trifluoromethyl;

[0149] wherein R^(g) is selected from H, C₁₋₃-alkyl, optionallysubstituted phenyl-C₁₋₃-alkyl, 4-6 membered heterocyclyl, and optionallysubstituted 4-6 membered heterocyclyl-C₁-C₃-alkyl,C₁₋₃-alkoxy-C₁₋₂-alkyl and C₁₋₃-alkoxy-C₁₋₃ -alkoxy-C₁₋₃-alkyl; and

[0150] where R⁸ is one or more substituents selected from halo, amino,nitro, hydroxy, C₁₋₆-alkyl, C₁₋₆-haloalkyl, C₁₋₆-alkoxy,C₁₋₆-haloalkoxy, C₁₋₆-aminoalkyl, C₁₋₆-hydroxyalkyl, optionallysubstituted phenyl, optionally substituted heterocyclyl, optionallysubstituted heterocyclyl-C₁₋₆-alkoxy, aminosulfonyl, C₃₋₆-cycloalkyl,C₁₋₆-alkylamino, C₁₋₆-alkylamino-C₁₋₆-alkyl, optionally substitutedheterocyclyl-C₁₋₆-alkylamino, optionally substitutedheterocyclyl-C₁₋₆-alkyl, C₁₋₆-alkylamino-C₂₋₄-alkynyl,C₁₋₆-alkylamino-C₁₋₆-alkoxy, C₁₋₆-alkylamino-C₁₋₆-alkoxy-C₁₋₆-alkoxy,and optionally substituted heterocyclyl-C₂₋₄-alkynyl, preferably chloro,fluoro, bromo, hydroxy, methoxy, ethoxy, —O—CH₂—O—, trifluoromethoxy,1-methylpiperidinylmethoxy, dimethylaminoethoxy, amino, dimethylamino,dimethylaminopropyl, diethylamino, aminosulfonyl, cyclohexyl,dimethylaminopropynyl, 3-(4-morpholinyl)propyn-1-yl,dimethylaminoethoxyethoxy, 3-(4-morpholinyl)propylamino, optionallysubstituted piperidinyl, morpholinyl, optionally substitutedpiperazinyl, optionally substituted phenyl, methyl, ethyl, propyl,cyano, hydroxymethyl, aminomethyl and trifluoromethyl, more preferablyfluoro, hydroxy, amino, and nitro, and particularly 4-fluoro; providedR²is not 3-trifluoromethylphenyl when R⁸ is 4-hydroxy, or 3-hydroxy.

[0151] A family of specific compounds of particular interest withinFormula I consists of compounds and pharmaceutically-acceptablederivatives thereof as follows:

[0152] 2-(3-Fluoro-benzylamino)-N-(4-phenoxy-phenyl)-nicotinamide;

[0153] 2-(3-Fluoro-benzylamino)-N-(4-phenoxy-phenyl)-nicotinamide,trifluoroacetate salt;

[0154]N-[4-tert-Butyl-3-(pyrrolidin-2-ylmethoxy)-phenyl]-2-(4-fluoro-benzylamino)-nicotinamide,hydrochloride salt;

[0155]N-(4-Phenoxy-phenyl)-2-(3-trifluoromethyl-benzylamino)-nicotinamide;

[0156] 2-(4-Fluoro-benzylamino)-N-(4-phenoxy-phenyl)-nicotinamide;

[0157]N-(4-Phenoxy-phenyl)-2-(4-trifluoromethyl-benzylamino)-nicotinamide;

[0158] 2-(2-Bromo-benzylamino)-N-(4-phenoxy-phenyl)-nicotinainide;

[0159]N-(4-Phenoxy-phenyl)-2-(4-trifluoromethoxy-benzylamino)-nicotinamide;

[0160] 2-(2,3-Difluoro-benzylamino)-N-(4-phenoxy-phenyl)-nicotinamide;

[0161]N-(4-Chlorophenyl)(2-{[(4-cyanophenyl)methyl]amino}(3-pyridyl))carboxamide;

[0162]N-(4-Chlorophenyl)(2-{[(2-cyanophenyl)methyl]amino}(3-pyridyl))carboxamide;

[0163] N-(4-sec-butylphenyl)-2-[(4-fluorobenzyl)amino]nicotinamide;

[0164] N-(4-tert-Butylphenyl)-2-[(4-fluorobenzyl)amino]nicotinamide;

[0165] N-(4-Isopropyl-phenyl)-2-(3-methoxy-benzylamino)-nicotinamide;

[0166](2-{[(3-Aminophenyl)methyl]amino}(3-pyridyl))-N-[4-(methylethyl)phenyl]carboxamide;

[0167](2-{[(4-Fluorophenyl)methyl]amino}(3-pyridyl))-N-[4-(methylethyl)phenyl]carboxamide;

[0168](2-{[(4-Fluorophenyl)methyl]amino}(3-pyridyl))-N-[3-(trifluoromethyl)phenyl]carboxamide;

[0169](2-{[(3,4-Dimethoxyphenyl)methyl]amino}(3-pyridyl))-N-[3-(trifluoromethyl)phenyl]carboxamide;

[0170]{2-[Benzylamino](3-pyridyl)}-N-[3-(trifluoromethyl)phenyl]-carboxamide;

[0171](2-{[(3-Chlorophenyl)methyl]amino}(3-pyridyl))-N-[3-(trifluoromethyl)phenyl]carboxamide;

[0172](2-{[(4-Bromophenyl)methyl]amino}(3-pyridyl))-N-[3-(trifluoromethyl)phenyl]carboxamide;

[0173](2-{[(4-Chlorophenyl)methyl]amino}(3-pyridyl))-N-[3-(trifluoromethyl)phenyl]carboxamide;

[0174](2-{[(2,4-Difluorophenyl)methyl]amino}(3-pyridyl))-N-[3-(trifluoromethyl)phenyl]carboxamide;

[0175](2-{[(4-Fluorophenyl)ethyl]amino}(3-pyridyl))-N-[3-(trifluoromethyl)phenyl]carboxamide;

[0176](2-{[(3,4-Difluorophenyl)methyl]amino}(3-pyridyl))-N-[3-(trifluoromethyl)phenyl]carboxamide;

[0177](2-{[(2,3-Difluorophenyl)methyl]amino}(3-pyridyl))-N-[3-(trifluoromethyl)phenyl]carboxamide;

[0178](2-{[(2-Fluorophenyl)methyl]amino}(3-pyridyl))-N-[3-(trifluoromethyl)phenyl]carboxamide;

[0179](2-{[(2,6-Difluorophenyl)methyl]amino}(3-pyridyl))-N-[3-(trifluoromethyl)phenyl]carboxamide;

[0180](2-{[(3-Bromophenyl)methyl]amino}(3-pyridyl))-N-[3-(trifluoromethyl)phenyl]carboxamide;

[0181](2-{[(4-Fluorophenyl)methyl]amino}(3-pyridyl))-N-[4-(trifluoromethyl)phenyl]carboxamide;

[0182]N-{3-[3-(Dimethylamino)propyl]-5-(trifluoromethyl)phenyl}(2-{[(4-fluorophenyl)methyl]amino}(3-pyridyl))carboxamide;

[0183]{2-[({3-[3-(Dimethylamino)propyl]-4-fluorophenyl}methyl)amino](3-pyridyl)}-N-[4-(tert-butyl)phenyl]carboxamide;

[0184]{2-[({3-[3-(Dimethylamino)propyl]-4-fluorophenyl}methyl)amino](3-pyridyl)}-N-[4-(trifluoromethyl)phenyl]carboxamide;

[0185]{2-[({3-[3-(Dimethylamino)propyl]-4-fluorophenyl}methyl)amino](3-pyridyl)}-N-(4-bromo-2-fluorophenyl)carboxamide;

[0186]2-[(4-Fluorobenzyl)amino]-N-[4-tert-butyl-3-(1,2,3,6-tetrahydropyridin-4-yl)phenyl]nicotinamide;and

[0187][2-({[4-Fluoro-3-(3-morpholin-4-ylprop-1-ynyl)phenyl]methyl}amino)(3-pyridyl)]-N-[3-(trifluoromethyl)phenyl]carboxamide.

[0188] Another family of specific compounds of particular interestwithin Formula I consists of compounds and pharmaceutically-acceptablederivatives thereof as follows:

[0189]N-(3,3-Dimethyl-1-(methylsulfonyl)-2,3-dihydro-1H-indol-6-yl)-2-(((4-fluorophenyl)methyl)amino)-3-pyridinecarboxamide;

[0190]N-(4-(1,1-dimethylethyl)-3-((N,N-dimethylglycyl)amino)phenyl)-2-(((4-fluorophenyl)methyl)amino)-3-pyridinecarboxamide;

[0191]N-(3-((((2R)-1-methyl-2-pyrrolidinyl)methyl)oxy)-5-(trifluoromethyl)phenyl)-2-((3-(1,3-oxazol-5-yl)phenyl)amino)-3-pyridinecarboxamide;

[0192]2-(((4-fluorophenyl)methyl)amino)-N-(3-((((2R)-1-methyl-2-pyrrolidinyl)methyl)oxy)-5-(trifluoromethyl)phenyl)-3-pyridinecarboxamide;

[0193]2-(((4-fluorophenyl)methyl)amino)-N-(3-((methylsulfonyl)amino)-5-(trifluoromethyl)phenyl)-3-pyridinecarboxamide;

[0194]2-((3-(1,3-oxazol-5-yl)phenyl)amino)-N-(3-(trifluoromethyl)phenyl)-3-pyridinecarboxamide;

[0195]2-(((4-fluorophenyl)methyl)amino)-N-(4-(1-methyl-1-(5-methyl-1,3,4-oxadiazol-2-yl)ethyl)phenyl)-3-pyridinecarboxamide;

[0196]3-(2-Chloro-5-{[2-(4-fluoro-benzylamino)-pyridine-3-carbonyl]-amino}-phenoxymethyl)-azetidine-1-carboxylicacid tert-butyl ester;

[0197]N-[3-(Azetidin-3-ylmethoxy)-4-chloro-phenyl]-2-(4-fluoro-benzylamino)-nicotinamide;

[0198] 6-Chloro-3-(4-fluoro-benzylamino)-pyridazine-4-carboxylic acid(4-tert-butyl-phenyl)-amide;

[0199] 3-(4-Fluoro-benzylamino)-pyridazine-4-carboxylic acid(4-tert-butyl-phenyl)-amide;

[0200]2-(4-Hydroxy-3-amino-benzylamino)-N-(4-isopropyl-phenyl)-nicotinamide;

[0201]2-(4-Hydroxy-3-nitro-benzylamino)-N-(4-isopropyl-phenyl)-nicotinamide;

[0202]3-(4-Fluoro-benzylamino)-1,2,5,6-tetrahydro-pyridazine-4-carboxylic acid(4-tert-butyl-phenyl)-amide; and

[0203]N-[3-(Azetidin-3-ylmethoxy)-5-trifluoromethyl-phenyl]-2-(4-fluoro-benzylamino)-nicotinamide.

[0204] Indications

[0205] Compounds of the present invention would be useful for, but notlimited to, the prevention or treatment of angiogenesis-relateddiseases. The compounds of the invention have kinase inhibitoryactivity, such as VEGFR/KDR inhibitory activity. The compounds of theinvention are useful in therapy as antineoplasia agents or to minimizedeleterious effects of VEGF.

[0206] Compounds of the invention would be useful for the treatment ofneoplasia including cancer and metastasis, including, but not limitedto: carcinoma such as cancer of the bladder, breast, colon, kidney,liver, lung (including small cell lung cancer), esophagus, gall-bladder,ovary, pancreas, stomach, cervix, thyroid, prostate, and skin (includingsquamous cell carcinoma); hematopoietic tumors of lymphoid lineage(including leukemia, acute lymphocitic leukemia, acute lymphoblasticleukemia, B-cell lymphoma, T-cell-lymphoma, Hodgkin's lymphoma,non-Hodgkin's lymphoma, hairy cell lymphoma and Burkett's lymphoma);hematopoietic tumors of myeloid lineage (including acute and chronicmyelogenous leukemias, myelodysplastic syndrome and promyelocyticleukemia); tumors of mesenchymal origin (including fibrosarcoma andrhabdomyosarcoma, and other sarcomas, e.g. soft tissue and bone); tumorsof the central and peripheral nervous system (including astrocytoma,neuroblastoma, glioma and schwannomas); and other tumors (includingmelanoma, seminoma, teratocarcinoma, osteosarcoma, xenoderomapigmentosum, keratoctanthoma, thyroid follicular cancer and Kaposi'ssarcoma).

[0207] Preferably, the compounds are useful for the treatment ofneoplasia selected from lung cancer, colon cancer and breast cancer.

[0208] The compounds also would be useful for treatment ofophthalmological conditions such as corneal graft rejection, ocularneovascularization, retinal neovascularization includingneovascularization following injury or infection, diabetic retinopathy,retrolental fibroplasia and neovascular glaucoma; retinal ischemia;vitreous hemorrhage; ulcerative diseases such as gastric ulcer;pathological, but non-malignant, conditions such as hemangiomas,including infantile hemaginomas, angiofibroma of the nasopharynx andavascular necrosis of bone; and disorders of the female reproductivesystem such as endometriosis. The compounds are also useful for thetreatment of edema, and conditions of vascular hyperpermeability.

[0209] The compounds of the invention are useful in therapy ofproliferative diseases. These compounds can be used for the treatment ofan inflammatory rheumatoid or rheumatic disease, especially ofmanifestations at the locomotor apparatus, such as various inflammatoryrheumatoid diseases, especially chronic polyarthritis includingrheumatoid arthritis, juvenile arthritis or psoriasis arthropathy;paraneoplastic syndrome or tumor-induced inflammatory diseases, turbideffusions, collagenosis, such as systemic Lupus erythematosus,poly-myositis, dermato-myositis, systemic sclerodermia or mixedcollagenosis; postinfectious arthritis (where no living pathogenicorganism can be found at or in the affected part of the body),seronegative spondylarthritis, such as spondylitis ankylosans;vasculitis, sarcoidosis, or arthrosis; or further any combinationsthereof. An example of an inflammation related disorder is (a) synovialinflammation, for example, synovitis, including any of the particularforms of synovitis, in particular bursal synovitis and purulentsynovitis, as far as it is not crystal-induced. Such synovialinflammation may for example, be consequential to or associated withdisease, e.g. arthritis, e.g. osteoarthritis, rheumatoid arthritis orarthritis deformans. The present invention is further applicable to thesystemic treatment of inflammation, e.g. inflammatory diseases orconditions, of the joints or locomotor apparatus in the region of thetendon insertions and tendon sheaths. Such inflammation may be, forexample, be consequential to or associated with disease or further (in abroader sense of the invention) with surgical intervention, including,in particular conditions such as insertion endopathy, myofascialesyndrome and tendomyosis. The present invention is further especiallyapplicable to the treatment of inflammation, e.g. inflammatory diseaseor condition, of connective tissues including dermatomyositis andmyositis.

[0210] These compounds can be used as active agents against such diseasestates as arthritis, atherosclerosis, psoriasis, hemangiomas, myocardialangiogenesis, coronary and cerebral collaterals, ischemic limbangiogenesis, wound healing, peptic ulcer Helicobacter related diseases,fractures, cat scratch fever, rubeosis, neovascular glaucoma andretinopathies such as those associated with diabetic retinopathy ormacular degeneration. In addition, some of these compounds can be usedas active agents against solid tumors, malignant ascites, hematopoieticcancers and hyperproliferative disorders such as thyroid hyperplasia(especially Grave's disease), and cysts (such as hypervascularity ofovarian stroma, characteristic of polycystic ovarian syndrome(Stein-Leventhal syndrome)) since such diseases require a proliferationof blood vessel cells for growth and/or metastasis.

[0211] Further, some of these compounds can be used as active agentsagainst burns, chronic lung disease, stroke, polyps, anaphylaxis,chronic and allergic inflammation, ovarian hyperstimulation syndrome,brain tumor-associated cerebral edema, high-altitude, trauma or hypoxiainduced cerebral or pulmonary edema, ocular and macular edema, ascites,and other diseases where vascular hyperpermeability, effusions,exudates, protein extravasation, or edema is a manifestation of thedisease. The compounds will also be useful in treating disorders inwhich protein extravasation leads to the deposition of fibrin andextracellular matrix, promoting stromal proliferation (e.g. fibrosis,cirrhosis and carpal tunnel syndrome).

[0212] The compounds of the present invention are also useful in thetreatment of ulcers including bacterial, fungal, Mooren ulcers andulcerative colitis.

[0213] The compounds of the present invention are also useful in thetreatment of conditions wherein undesired angiogenesis, edema, orstromal deposition occurs in viral infections such as Herpes simplex,Herpes Zoster, AIDS, Kaposi's sarcoma, protozoan infections andtoxoplasmosis, following trauma, radiation, stroke, endometriosis,ovarian hyperstimulation syndrome, systemic lupus, sarcoidosis,synovitis, Crohn's disease, sickle cell anaemia, Lyme disease,pemphigoid, Paget's disease, hyperviscosity syndrome, Osler-Weber-Rendudisease, chronic inflammation, chronic occlusive pulmonary disease,asthma, and inflammatory rheumatoid or rheumatic disease. The compoundsare also useful in the reduction of sub-cutaneous fat and for thetreatment of obesity.

[0214] The compounds of the present invention are also useful in thetreatment of ocular conditions such as ocular and macular edema,glaucoma, ocular neovascular disease, scleritis, radial keratotomy,uveitis, vitritis, myopia, optic pits, chronic retinal detachment,post-laser complications, conjunctivitis, Stargardt's disease and Ealesdisease in addition to retinopathy and macular degeneration.

[0215] The compounds of the present invention are also useful in thetreatment of cardiovascular conditions such as atherosclerosis,restenosis, arteriosclerosis, vascular occlusion and carotid obstructivedisease.

[0216] The compounds of the present invention are also useful in thetreatment of cancer related indications such as solid tumors, sarcomas(especially Ewing's sarcoma and osteosarcoma), retinoblastoma,rhabdomyosarcomas, neuroblastoma, hematopoietic malignancies, includingleukemia and lymphoma, tumor-induced pleural or pericardial effusions,and malignant ascites.

[0217] The compounds of the present invention are also useful in thetreatment of diabetic conditions such as diabetic retinopathy andmicroangiopathy.

[0218] The compounds of this invention may also act as inhibitors ofother protein kinases, e.g. p38, EGFR, CDK-2, CDK-5, IKK, JNK3, bFGFR,PDGFR and RAF and thus be effective in the treatment of diseasesassociated with other protein kinases.

[0219] Besides being useful for human treatment, these compounds arealso useful for veterinary treatment of companion animals, exoticanimals and farm animals, including mammals, rodents, and the like. Morepreferred animals include horses, dogs, and cats.

[0220] As used herein, the compounds of the present invention includethe pharmaceutically acceptable derivatives thereof.

[0221] Definitions

[0222] A “pharmaceutically-acceptable derivative” denotes any salt,ester of a compound of this invention, or any other compound which uponadministration to a patient is capable of providing (directly orindirectly) a compound of this invention, or a metabolite or residuethereof, characterized by the ability to inhibit angiogenesis.

[0223] The term “treatment” includes therapeutic treatment as well asprophylactic treatment (either preventing the onset of disordersaltogether or delaying the onset of a preclinically evident stage ofdisorders in individuals).

[0224] The phrase “therapeutically-effective” is intended to qualify theamount of each agent, which will achieve the goal of improvement indisorder severity and the frequency of incidence over treatment of eachagent by itself, while avoiding adverse side effects typicallyassociated with alternative therapies. For example, effective neoplastictherapeutic agents prolong the survivability of the patient, inhibit therapidly-proliferating cell growth associated with the neoplasm, oreffect a regression of the neoplasm.

[0225] The term “prevention” includes either preventing the onset ofdisorders altogether or delaying the onset of a preclinically evidentstage of disorders in individuals. This includes prophylactic treatmentof those at risk of developing a disease, such as a cancer, for example.“Prophylaxis” is another term for prevention.

[0226] The term “H” denotes a single hydrogen atom. This radical may beattached, for example, to an oxygen atom to form a hydroxyl radical.

[0227] Where the term “alkyl” is used, either alone or within otherterms such as “haloalkyl” and “alkylamino”, it embraces linear orbranched radicals having one to about twelve carbon atoms. Morepreferred alkyl radicals are “lower alkyl” radicals having one to aboutsix carbon atoms. Examples of such radicals include methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl,isoamyl, hexyl and the like. Even more preferred are lower alkylradicals having one or two carbon atoms. The term “alkylenyl” embracesbridging divalent alkyl radicals such as methylenyl and ethylenyl. Theterm “lower alkyl substituted with R¹” does not include an acetalmoiety.

[0228] The term “alkenyl” embraces linear or branched radicals having atleast one carbon-carbon double bond of two to about twelve carbon atoms.More preferred alkenyl radicals are “lower alkenyl” radicals having twoto about six carbon atoms. Most preferred lower alkenyl radicals areradicals having two to about four carbon atoms. Examples of alkenylradicals include ethenyl, propenyl, allyl, propenyl, butenyl and4-methylbutenyl. The terms “alkenyl” and “lower alkenyl”, embraceradicals having “cis” and “trans” orientations, or alternatively, “E”and “Z” orientations.

[0229] The term “alkynyl” denotes linear or branched radicals having atleast one carbon-carbon triple bond and having two to about twelvecarbon atoms. More preferred alkynyl radicals are “lower alkynyl”radicals having two to about six carbon atoms. Most preferred are loweralkynyl radicals having two to about four carbon atoms. Examples of suchradicals include propargyl, butynyl, and the like.

[0230] The term “halo” means halogens such as fluorine, chlorine,bromine or iodine atoms.

[0231] The term “haloalkyl” embraces radicals wherein any one or more ofthe alkyl carbon atoms is substituted with halo as defined above.Specifically embraced are monohaloalkyl, dihaloalkyl and polyhaloalkylradicals including perhaloalkyl. A monohaloalkyl radical, for oneexample, may have either an iodo, bromo, chloro or fluoro atom withinthe radical. Dihalo and polyhaloalkyl radicals may have two or more ofthe same halo atoms or a combination of different halo radicals. “Lowerhaloalkyl” embraces radicals having 1-6 carbon atoms. Even morepreferred are lower haloalkyl radicals having one to three carbon atoms.Examples of haloalkyl radicals include fluoromethyl, difluoromethyl,trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl,pentafluoroethyl, heptafluoropropyl, difluorochloromethyl,dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl anddichloropropyl. “Perfluoroalkyl” means alkyl radicals having allhydrogen atoms replaced with fluoro atoms. Examples includetrifluoromethyl and pentafluoroethyl.

[0232] The term “hydroxyalkyl” embraces linear or branched alkylradicals having one to about ten carbon atoms any one of which may besubstituted with one or more hydroxyl radicals. More preferredhydroxyalkyl radicals are “lower hydroxyalkyl” radicals having one tosix carbon atoms and one or more hydroxyl radicals. Examples of suchradicals include hydroxymethyl, hydroxyethyl, hydroxypropyl,hydroxybutyl and hydroxyhexyl. Even more preferred are lowerhydroxyalkyl radicals having one to three carbon atoms.

[0233] The term “alkoxy” embrace linear or branched oxy-containingradicals each having alkyl portions of one to about ten carbon atoms.More preferred alkoxy radicals are “lower alkoxy” radicals having one tosix carbon atoms. Examples of such radicals include methoxy, ethoxy,propoxy, butoxy and tert-butoxy. Even more preferred are lower alkoxyradicals having one to three carbon atoms. Alkoxy radicals may befurther substituted with one or more halo atoms, such as fluoro, chloroor bromo, to provide “haloalkoxy” radicals. Even more preferred arelower haloalkoxy radicals having one to three carbon atoms. Examples ofsuch radicals include fluoromethoxy, chloromethoxy, trifluoromethoxy,trifluoroethoxy, fluoroethoxy and fluoropropoxy.

[0234] The term “aryl”, alone or in combination, means a carbocyclicaromatic system containing one or two rings wherein such rings may beattached together in a fused manner. The term “aryl” embraces aromaticradicals such as phenyl, naphthyl, indenyl, tetrahydronaphthyl, andindanyl. More preferred aryl is phenyl. Said “aryl” group may have 1 to3 substituents such as lower alkyl, hydroxyl, halo, haloalkyl, nitro,cyano, alkoxy and lower alkylamino. Phenyl substituted with —O—CH₂—O—forms the aryl benzodioxolyl substituent.

[0235] The term “heterocyclyl” embraces saturated, partially saturatedand unsaturated heteroatom-containing ring radicals, where theheteroatoms may be selected from nitrogen, sulfur and oxygen. It doesnot include rings containing —O—O—, —O—S— or —S—S— portions. Said“heterocyclyl” group may have 1 to 3 substituents such as hydroxyl, Boc,halo, haloalkyl, cyano, lower alkyl, lower aralkyl, oxo, lower alkoxy,amino and lower alkylamino.

[0236] Examples of saturated heterocyclic radicals include saturated 3to 6-membered heteromonocyclic groups containing 1 to 4 nitrogen atoms[e.g. pyrrolidinyl, imidazolidinyl, piperidinyl, pyrrolinyl,piperazinyl]; saturated 3 to 6-membered heteromonocyclic groupcontaining 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms [e.g.morpholinyl]; saturated 3 to 6-membered heteromonocyclic groupcontaining 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms [e.g.,thiazolidinyl]. Examples of partially saturated heterocyclyl radicalsinclude dihydrothienyl, dihydropyranyl, dihydrofuryl anddihydrothiazolyl.

[0237] Examples of unsaturated heterocyclic radicals, also termed“heteroaryl” radicals, include unsaturated 5 to 6 memberedheteromonocyclyl group containing 1 to 4 nitrogen atoms, for example,pyrrolyl, imidazolyl, pyrazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl,pyrimidyl, pyrazinyl, pyridazinyl, triazolyl [e.g., 4H-1,2,4-triazolyl,1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl]; unsaturated 5- to 6-memberedheteromonocyclic group containing an oxygen atom, for example, pyranyl,2-furyl, 3-furyl, etc.; unsaturated 5 to 6-membered heteromonocyclicgroup containing a sulfur atom, for example, 2-thienyl, 3-thienyl, etc.;unsaturated 5- to 6-membered heteromonocyclic group containing 1 to 2oxygen atoms and 1 to 3 nitrogen atoms, for example, oxazolyl,isoxazolyl, oxadiazolyl [e.g., 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl,1,2,5-oxadiazolyl]; unsaturated 5 to 6-membered heteromonocyclic groupcontaining 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, for example,thiazolyl, thiadiazolyl 3[e.g., 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl,1,2,5-thiadiazolyl].

[0238] The term also embraces radicals where heterocyclic radicals arefused/condensed with aryl radicals: unsaturated condensed heterocyclicgroup containing 1 to 5 nitrogen atoms, for example, indolyl,isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl,indazolyl, benzotriazolyl, tetrazolopyridazinyl [e.g., tetrazolo[1,5-b]pyridazinyl]; unsaturated condensed heterocyclic group containing1 to 2 oxygen atoms and 1 to 3 nitrogen atoms [e.g. benzoxazolyl,benzoxadiazolyl]; unsaturated condensed heterocyclic group containing 1to 2 sulfur atoms and 1 to 3 nitrogen atoms [e.g., benzothiazolyl,benzothiadiazolyl]; and saturated, partially unsaturated and unsaturatedcondensed heterocyclic group containing 1 to 2 oxygen or sulfur atoms[e.g. benzofuryl, benzothienyl, 2,3-dihydro-benzo[1,4]dioxinyl anddihydrobenzofuryl]. Preferred heterocyclic radicals include five to tenmembered fused or unfused radicals. More preferred examples ofheteroaryl radicals include quinolyl, isoquinolyl, imidazolyl, pyridyl,thienyl, thiazolyl, oxazolyl, furyl, and pyrazinyl. Other preferredheteroaryl radicals are 5- or 6-membered heteroaryl, containing one ortwo heteroatoms selected from sulfur, nitrogen and oxygen, selected fromthienyl, furyl, pyrrolyl, indazolyl, pyrazolyl, oxazolyl, triazolyl,imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, pyridyl, piperidinyland pyrazinyl.

[0239] Particular examples of non-nitrogen containing heteroaryl includepyranyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, benzofuryl,benzothienyl, and the like.

[0240] Particular examples of partially saturated and saturatedheterocyclyl include pyrrolidinyl, imidazolidinyl, piperidinyl,pyrrolinyl, pyrazolidinyl, piperazinyl, morpholinyl, tetrahydropyranyl,thiazolidinyl, dihydrothienyl, 2,3-dihydro-benzo[1,4]dioxanyl,indolinyl, isoindolinyl, dihydrobenzothienyl, dihydrobenzofuryl,isochromanyl, chromanyl, 1,2-dihydroquinolyl,1,2,3,4-tetrahydro-isoquinolyl, 1,2,3,4-tetrahydro-quinolyl,2,3,4,4a,9,9a-hexahydro-1H-3-aza-fluorenyl,5,6,7-trihydro-1,2,4-triazolo[3,4-a]isoquinolyl,3,4-dihydro-2H-benzo[1,4]oxazinyl, benzo[1,4]dioxanyl,2,3-dihydro-1H-1λ′-benzo[d]isothiazol-6-yl, dihydropyranyl, dihydrofuryland dihydrothiazolyl, and the like.

[0241] The term “sulfonyl”, whether used alone or linked to other termssuch as alkylsulfonyl, denotes respectively divalent radicals —SO₂—.

[0242] The terms “sulfamyl,” “aminosulfonyl” and “sulfonamidyl,” denotesa sulfonyl radical substituted with an amine radical, forming asulfonamide (—SO₂NH₂)

[0243] The term “alkylaminosulfonyl” includes “N-alkylaminosulfonyl”where sulfamyl radicals are independently substituted with one or twoalkyl radical(s). More preferred alkylaminosulfonyl radicals are “loweralkylaminosulfonyl” radicals having one to six carbon atoms. Even morepreferred are lower alkylaminosulfonyl radicals having one to threecarbon atoms. Examples of such lower alkylaminosulfonyl radicals includeN-methylaminosulfonyl, and N-ethylaminosulfonyl.

[0244] The terms “carboxy” or “carboxyl”, whether used alone or withother terms, such as “carboxyalkyl”, denotes —CO₂H.

[0245] The term “carbonyl”, whether used alone or with other terms, suchas “aminocarbonyl”, denotes —(C═O)—.

[0246] The term “aminocarbonyl” denotes an amide group of the formula—C(═O)NH₂.

[0247] The terms “N-alkylaminocarbonyl” and “N,N-dialkylaminocarbonyl”denote aminocarbonyl radicals independently substituted with one or twoalkyl radicals, respectively. More preferred are “loweralkylaminocarbonyl” having lower alkyl radicals as described aboveattached to an aminocarbonyl radical.

[0248] The terms “N-arylaminocarbonyl” and “N-alkyl-N-arylaminocarbonyl”denote aminocarbonyl radicals substituted, respectively, with one arylradical, or one alkyl and one aryl radical.

[0249] The term “heterocyclylcarbonylalkyl” denotes alkyl groups whichhave been substituted with a heterocyclylcarbonyl radical. Morepreferred are contain 4-6 membered heterocyclyl groups and C₁-C₆-alkylradicals, such as 4-methylpiperazinylcarbonylethyl.

[0250] The term “heterocyclylalkylcarbonyl” denotes carbonyl groupswhich have been substituted with a heterocyclylalkyl radical. Morepreferred are contain 4-6 membered heterocyclyl groups and C₁-C₆-alkylradicals, such as piperidinylmethylcarbonyl.

[0251] The term “alkoxycarbonylaminoalkyl” denotes an aminoalkyl group,which is substituted with an alkoxycarbonyl radical. More preferred are“lower alkoxycarbonylaminoalkyl” having C₁-C₆-alkyl radicals.

[0252] The term “heterocyclylalkylenyl” embracesheterocyclic-substituted alkyl radicals. More preferredheterocyclylalkylenyl radicals are “5- or 6-memberedheteroarylalkylenyl” radicals having alkyl portions of one to six carbonatoms and a 5- or 6-membered heteroaryl radical. Even more preferred arelower heteroarylalkylenyl radicals having alkyl portions of one to fourcarbon atoms. Examples include such radicals as pyridylmethyl andthienylmethyl.

[0253] The term “aralkyl” embraces aryl-substituted alkyl radicals.Preferable aralkyl radicals are “lower aralkyl” radicals having arylradicals attached to alkyl radicals having one to six carbon atoms. Evenmore preferred are “phenylalkylenyl” attached to alkyl portions havingone to three carbon atoms. Examples of such radicals include benzyl,diphenylmethyl and phenylethyl. The aryl in said aralkyl may beadditionally substituted with halo, alkyl, alkoxy, halkoalkyl andhaloalkoxy.

[0254] The term “alkylthio” embraces radicals containing a linear orbranched alkyl radical, of one to ten carbon atoms, attached to adivalent sulfur atom. Even more preferred are lower alkylthio radicalshaving one to three carbon atoms. An example of “alkylthio” ismethylthio, (CH₃S—).

[0255] The term “haloalkylthio” embraces radicals containing a haloalkylradical, of one to ten carbon atoms, attached to a divalent sulfur atom.Even more preferred are lower haloalkylthio radicals having one to threecarbon atoms. An example of “haloalkylthio” is trifluoromethylthio.

[0256] The term “alkylamino” embraces “N-alkylamino” and“N,N-dialkylamino” where amino groups are independently substituted withone alkyl radical and with two alkyl radicals, respectively. Morepreferred alkylamino radicals are “lower alkylamino” radicals having oneor two alkyl radicals of one to six carbon atoms, attached to a nitrogenatom. Even more preferred are lower alkylamino radicals having one tothree carbon atoms. Suitable alkylamino radicals may be mono ordialkylamino such as N-methylamino, N-ethylamino, N,N-dimethylamino,N,N-diethylamino and the like.

[0257] The term “arylamino” denotes amino groups which have beensubstituted with one or two aryl radicals, such as N-phenylamino. Thearylamino radicals may be further substituted on the aryl ring portionof the radical.

[0258] The term “heteroarylamino” denotes amino groups which have beensubstituted with one or two heteroaryl radicals, such as N-thienylamino.The “heteroarylamino” radicals may be further substituted on theheteroaryl ring portion of the radical.

[0259] The term “aralkylamino” denotes amino groups which have beenindependently substituted with one or two aralkyl radicals. Morepreferred are phenyl-C₁-C₃-alkylamino radicals, such as N-benzylamino.The aralkylamino radicals may be further substituted on the aryl ringportion.

[0260] The terms “N-alkyl-N-arylamino” and “N-aralkyl-N-alkylamino”denote amino groups which are independently substituted with one aralkyland one alkyl radical, or one aryl and one alkyl radical, respectively,to an amino group.

[0261] The term “aminoalkyl” embraces linear or branched alkyl radicalshaving one to about ten carbon atoms any one of which may be substitutedwith one or more amino radicals. More preferred aminoalkyl radicals are“lower aminoalkyl” radicals having one to six carbon atoms and one ormore amino radicals. Examples of such radicals include aminomethyl,aminoethyl, aminopropyl, aminobutyl and aminohexyl. Even more preferredare lower aminoalkyl radicals having one to three carbon atoms.

[0262] The term “alkylaminoalkyl” embraces alkyl radicals substitutedwith alkylamino radicals. More preferred alkylaminoalkyl radicals are“lower alkylaminoalkyl” radicals having alkyl radicals of one to sixcarbon atoms. Even more preferred are lower alkylaminoalkyl radicalshaving alkyl radicals of one to three carbon atoms. Suitablealkylaminoalkyl radicals may be mono or dialkyl substituted, such asN-methylaminomethyl, N,N-dimethyl-aminoethyl, N,N-diethylaminomethyl andthe like.

[0263] The term “alkylaminoalkoxy” embraces alkoxy radicals substitutedwith alkylamino radicals. More preferred alkylaminoalkoxy radicals are“lower alkylaminoalkoxy” radicals having alkoxy radicals of one to sixcarbon atoms. Even more preferred are lower alkylaminoalkoxy radicalshaving alkyl radicals of one to three carbon atoms. Suitablealkylaminoalkoxy radicals may be mono or dialkyl substituted, such asN-methylaminoethoxy, N,N-dimethylaminoethoxy, N,N-diethylaminoethoxy andthe like.

[0264] The term “alkylaminoalkoxyalkoxy” embraces alkoxy radicalssubstituted with alkylaminoalkoxy radicals. More preferredalkylaminoalkoxyalkoxy radicals are “lower alkylaminoalkoxyalkoxy”radicals having alkoxy radicals of one to six carbon atoms. Even morepreferred are lower alkylaminoalkoxyalkoxy radicals having alkylradicals of one to three carbon atoms. Suitable alkylaminoalkoxyalkoxyradicals may be mono or dialkyl substituted, such asN-methylaminoethoxyethoxy, N-methylaminomethoxyethoxy,N,N-dimethylaminoethoxyethoxy, N,N-diethylaminomethoxymethoxy and thelike.

[0265] The term “carboxyalkyl” embraces linear or branched alkylradicals having one to about ten carbon atoms any one of which may besubstituted with one or more carboxy radicals. More preferredcarboxyalkyl radicals are “lower carboxyalkyl” radicals having one tosix carbon atoms and one carboxy radical. Examples of such radicalsinclude carboxymethyl, carboxypropyl, and the like. Even more preferredare lower carboxyalkyl radicals having one to three CH₂ groups.

[0266] The term “halosulfonyl” embraces sulfonyl radicals substitutedwith a halogen radical. Examples of such halosulfonyl radicals includechlorosulfonyl and fluorosulfonyl.

[0267] The term “arylthio” embraces aryl radicals of six to ten carbonatoms, attached to a divalent sulfur atom. An example of “arylthio” isphenylthio.

[0268] The term “aralkylthio” embraces aralkyl radicals as describedabove, attached to a divalent sulfur atom. More preferred arephenyl-C₁-C₃-alkylthio radicals. An example of “aralkylthio” isbenzylthio.

[0269] The term “aryloxy” embraces optionally substituted aryl radicals,as defined above, attached to an oxygen atom. Examples of such radicalsinclude phenoxy.

[0270] The term “aralkoxy” embraces oxy-containing aralkyl radicalsattached through an oxygen atom to other radicals. More preferredaralkoxy radicals are “lower aralkoxy” radicals having optionallysubstituted phenyl radicals attached to lower alkoxy radical asdescribed above.

[0271] The term “heteroaryloxy” embraces optionally substitutedheteroaryl radicals, as defined above, attached to an oxygen atom.

[0272] The term “heteroarylalkoxy” embraces oxy-containingheteroarylalkyl radicals attached through an oxygen atom to otherradicals. More preferred heteroarylalkoxy radicals are “lowerheteroarylalkoxy” radicals having optionally substituted heteroarylradicals attached to lower alkoxy radical as described above.

[0273] The term “cycloalkyl” includes saturated carbocyclic groups.Preferred cycloalkyl groups include C₃-C₆ rings. More preferredcompounds include, cyclopentyl, cyclopropyl, and cyclohexyl.

[0274] The term “cycloalkylalkyl” embraces cycloalkyl-substituted alkylradicals. Preferable cycloalkylalkyl radicals are “lowercycloalkylalkyl” radicals having C₃₋₆ cycloalkyl radicals attached toalkyl radicals having one to six carbon atoms.

[0275] The term “cycloalkenyl” includes carbocyclic groups having one ormore carbon-carbon double bonds including “cycloalkyldienyl” compounds.Preferred cycloalkenyl groups include C₃-C₆ rings. More preferredcompounds include, for example, cyclopentenyl, cyclopentadienyl,cyclohexenyl and cycloheptadienyl.

[0276] The term “comprising” is meant to be open ended, including theindicated component but not excluding other elements.

[0277] The term “Formulas I-IV” includes formula II′.

[0278] The compounds of the invention are endowed with kinase inhibitoryactivity, such as KDR inhibitory activity.

[0279] The present invention also comprises the use of a compound of theinvention, or pharmaceutically acceptable salt thereof, in themanufacture of a medicament for the treatment either acutely orchronically of an angiogenesis mediated disease state, including thosedescribed previously. The compounds of the present invention are usefulin the manufacture of an anti-cancer medicament. The compounds of thepresent invention are also useful in the manufacture of a medicament toattenuate or prevent disorders through inhibition of KDR.

[0280] The present invention comprises a pharmaceutical compositioncomprising a therapeutically-effective amount of a compound of FormulasI-IV in association with a least one pharmaceutically-acceptablecarrier, adjuvant or diluent.

[0281] The present invention also comprises a method of treatingangiogenesis related disorders in a subject having or susceptible tosuch disorder, the method comprising treating the subject with atherapeutically-effective amount of a compound of Formula I

[0282] wherein each of A¹ and A² is independently C or N;

[0283] wherein A¹-A² form part of a ring A selected from 5- or6-membered heteroaryl;

[0284] wherein X is

[0285] wherein Z is oxygen or sulfur;

[0286] Y is selected from

[0287] wherein p is 0 to 2,

[0288] wherein R^(a) and R^(b) are independently selected from H, halo,cyano, —NHR⁶ and C₁₋₄-alkyl substituted with R¹, or wherein R^(a) andR^(b) together form C₃-C₆ cycloalkyl;

[0289] wherein R^(z) is selected from C₂-C₆-alkylenyl, where one of theCH₂ groups may be replaced with an oxygen atom or an —NH—; wherein oneof the CH₂ groups may be substituted with one or two radicals selectedfrom halo, cyano, —NHR⁶ and C₁₋₄-alkyl substituted with R¹;

[0290] wherein R^(d) is cycloalkyl;

[0291] wherein R¹ is one or more substituents independently selectedfrom H, halo, —OR⁷, oxo, —SR⁷, —CO₂R⁷, —COR⁷, —CONR⁷R⁷, —NR⁷R⁷,—SO₂NR⁷R⁷, —NR⁷C(O)OR⁷, —NR⁷C(O)R⁷, —NR⁷C(O)NR⁷R⁷, cycloalkyl,optionally substituted phenylalkylenyl, optionally substituted 5-6membered heterocyclyl, optionally substituted heteroarylalkylenyl,optionally substituted phenyl, lower alkyl, cyano, lower hydroxyalkyl,lower carboxyalkyl, nitro, lower alkenyl, lower alkynyl, loweraminoalkyl, lower alkylaminoalkyl and lower haloalkyl;

[0292] wherein R² is selected from

[0293] a) substituted or unsubstituted 6-10 membered aryl,

[0294] b) substituted or unsubstituted 5-6 membered heterocyclyl,

[0295] c) substituted or unsubstituted 9-14 membered bicyclic ortricyclic heterocyclyl,

[0296] d) cycloalkyl, and

[0297] e) cycloalkenyl,

[0298] wherein substituted R² is substituted with one or moresubstituents independently selected from halo, —OR⁷, —SR⁷, —CO₂R⁷—CONR⁷R⁷, —COR⁷, —NR⁷R⁷, —NH(C₁—C₄ alkylenylR⁹), —SO₂R⁷, —SO₂NR⁷R⁷,—NR⁷C(O)OR⁷, —NR⁷C(O)R⁷, optionally substituted cycloalkyl, optionallysubstituted 5-6 membered heterocyclyl, optionally substituted phenyl,halosulfonyl, cyano, alkylaminoalkoxy, alkylaminoalkoxyalkoxy, nitro,lower alkyl substituted with R¹, lower alkenyl substituted with R¹, andlower alkynyl substituted with Rl;

[0299] wherein R³ is selected from aryl substituted with one or moresubstituents independently selected from halo, —OR₇, —SR⁷, —SO₂R⁷,—CO₂R⁷, —CONR⁷R⁷, —COR⁷, —NR⁷R⁷, —SO₂NR⁷R⁷, —NR⁷C(O)OR⁷, —NR⁷C(O)R⁷,cycloalkyl, optionally substituted 5-6 membered heterocyclyl, optionallysubstituted phenyl, nitro, alkylaminoalkoxyalkoxy, cyano,alkylaminoalkoxy, lower alkyl substituted with R¹, lower alkenylsubstituted with R¹, and lower alkynyl substituted with R¹;

[0300] wherein R⁴ is selected from a direct bond, C₂₋₄-alkylenyl,C₂₋₄-alkenylenyl and C₂₋₄-alkynylenyl, where one of the CH₂ groups maybe substituted with an oxygen atom or an —NH—,

[0301] wherein R⁴ is optionally substituted with hydroxy;

[0302] wherein R⁵ is selected from H, lower alkyl, phenyl and loweraralkyl;

[0303] wherein R^(5a) is selected from H, lower alkyl, phenyl and loweraralkyl;

[0304] wherein R⁶ is selected from H or C₁₋₆-alkyl; and

[0305] wherein R⁷ is selected from H, lower alkyl, phenyl, 5-6 memberedheterocyclyl, C₃-C₆-cycloalkyl, phenylalkyl, 5-6 memberedheterocyclylalkyl, C₃-C₆ cycloalkylalkyl, and lower haloalkyl;

[0306] wherein R⁹ is selected from H, phenyl, 5-6 membered heterocyclyland C₃-C₆ cycloalkyl.

[0307] Combinations

[0308] While the compounds of the invention can be administered as thesole active pharmaceutical agent, they can also be used in combinationwith one or more compounds of the invention or other agents. Whenadministered as a combination, the therapeutic agents can be formulatedas separate compositions that are administered at the same time orsequentially at different times, or the therapeutic agents can be givenas a single composition.

[0309] The phrase “co-therapy” (or “combination-therapy”), in defininguse of a compound of the present invention and another pharmaceuticalagent, is intended to embrace administration of each agent in asequential manner in a regimen that will provide beneficial effects ofthe drug combination, and is intended as well to embraceco-administration of these agents in a substantially simultaneousmanner, such as in a single capsule having a fixed ratio of these activeagents or in multiple, separate capsules for each agent.

[0310] Specifically, the administration of compounds of the presentinvention may be in conjunction with additional therapies known to thoseskilled in the art in the prevention or treatment of neoplasia, such aswith radiation therapy or with cytostatic or cytotoxic agents.

[0311] If formulated as a fixed dose, such combination products employthe compounds of this invention within the accepted dosage ranges.Compounds of Formulas I-IV may also be administered sequentially withknown anticancer or cytotoxic agents when a combination formulation isinappropriate. The invention is not limited in the sequence ofadministration; compounds of the invention may be administered eitherprior to, simultaneous with, or after administration of the knownanticancer or cytotoxic agent.

[0312] Currently, standard treatment of primary tumors consists ofsurgical excision followed by either radiation or IV administeredchemotherapy. The typical chemotherapy regime consists of either DNAalkylating agents, DNA intercalating agents, CDK inhibitors, ormicrotubule poisons. The chemotherapy doses used are just below themaximal tolerated dose and therefore dose limiting toxicities typicallyinclude, nausea, vomiting, diarrhea, hair loss, neutropenia and thelike.

[0313] There are large numbers of antineoplastic agents available incommercial use, in clinical evaluation and in pre-clinical development,which would be selected for treatment of neoplasia by combination drugchemotherapy. Such antineoplastic agents fall into several majorcategories, namely, antibiotic-type agents, alkylating agents,antimetabolite agents, hormonal agents, immunological agents,interferon-type agents and a category of miscellaneous agents.

[0314] A first family of antineoplastic agents which may be used incombination with compounds of the present invention consists ofantimetabolite-type/thymidilate synthase inhibitor antineoplasticagents. Suitable antimetabolite antineoplastic agents may be selectedfrom but not limited to the group consisting of 5-FU-fibrinogen,acanthifolic acid, aminothiadiazole, brequinar sodium, carmofur,Ciba-Geigy CGP-30694, cyclopentyl cytosine, cytarabine phosphatestearate, cytarabine conjugates, Lilly DATHF, Merrel Dow DDFC,dezaguanine, dideoxycytidine, dideoxyguanosine, didox, Yoshitomi DMDC,doxifluridine, Wellcome EHNA, Merck & Co. EX-015, fazarabine,floxuridine, fludarabine phosphate, 5-fluorouracil,N-(2′-furanidyl)-5-fluorouracil, Daiichi Seiyaku FO-152, isopropylpyrrolizine, Lilly LY-188011, Lilly LY-264618, methobenzaprim,methotrexate, Wellcome MZPES, norspermidine, NCI NSC-127716, NCINSC-264880, NCI NSC-39661, NCI NSC-612567, Warner-Lambert PALA,pentostatin, piritrexim, plicamycin, Asahi Chemical PL-AC, TakedaTAC-788, thioguanine, tiazofurin, Erbamont TIF, trimetrexate, tyrosinekinase inhibitors, Taiho UFT and uricytin.

[0315] A second family of antineoplastic agents which may be used incombination with compounds of the present invention consists ofalkylating-type antineoplastic agents. Suitable alkylating-typeantineoplastic agents may be selected from but not limited to the groupconsisting of Shionogi 254-S, aldo-phosphamide analogues, altretamine,anaxirone, Boehringer Mannheim BBR-2207, bestrabucil, budotitane,Wakunaga CA-102, carboplatin, carmustine, Chinoin-139, Chinoin-153,chlorambucil, cisplatin, cyclophosphamide, American Cyanamid CL-286558,Sanofi CY-233, cyplatate, Degussa D-19-384, Sumimoto DACHP(Myr)2,diphenylspiromustine, diplatinum cytostatic, Erba distamycinderivatives, Chugai DWA-2114R, ITI E09, elmustine, Erbamont FCE-24517,estramustine phosphate sodium, fotemustine, Unimed G-6-M, ChinoinGYKI-17230, hepsul-fam, ifosfamide, iproplatin, lomustine, mafosfamide,mitolactol, Nippon Kayaku NK-121, NCI NSC-264395, NCI NSC-342215,oxaliplatin, Upjohn PCNU, prednimustine, Proter PTT-119, ranimustine,semustine, SmithKline SK&F-101772, Yakult Honsha SN-22, spiromus-tine,Tanabe Seiyaku TA-077, tauromustine, temozolomide, teroxirone,tetraplatin and trimelamol.

[0316] A third family of antineoplastic agents which may be used incombination with compounds of the present invention consists ofantibiotic-type antineoplastic agents. Suitable antibiotic-typeantineoplastic agents may be selected from but not limited to the groupconsisting of Taiho 4181-A, aclarubicin, actinomycin D, actinoplanone,Erbamont ADR-456, aeroplysinin derivative, Ajinomoto AN-201-II,Ajinomoto AN-3, Nippon Soda anisomycins, anthracycline, azino-mycin-A,bisucaberin, Bristol-Myers BL-6859, Bristol-Myers BMY-25067,Bristol-Myers BMY-25551, Bristol-Myers BMY-26605, Bristol-MyersBMY-27557, Bristol-Myers BMY-28438, bleomycin sulfate, bryostatin-1,Taiho C-1027, calichemycin, chromoximycin, dactinomycin, daunorubicin,Kyowa Hakko DC-102, Kyowa Hakko DC-79, Kyowa Hakko DC-88A, Kyowa HakkoDC89-A1, Kyowa Hakko DC92-B, ditrisarubicin B, Shionogi DOB-41,doxorubicin, doxorubicin-fibrinogen, elsamicin-A, epirubicin, erbstatin,esorubicin, esperamicin-A1, esperamicin-A1b, Erbamont FCE-21954,Fujisawa FK-973, fostriecin, Fujisawa FR-900482, glidobactin,gregatin-A, grincamycin, herbimycin, idarubicin, illudins, kazusamycin,kesarirhodins, Kyowa Hakko KM-5539, Kirin Brewery KRN-8602, Kyowa HakkoKT-5432, Kyowa Hakko KT-5594, Kyowa Hakko KT-6149, American CyanamidLL-D49194, Meiji Seika ME 2303, menogaril, mitomycin, mitoxantrone,SmithKline M-TAG, neoenactin, Nippon Kayaku NK-313, Nippon KayakuNKT-01, SRI International NSC-357704, oxalysine, oxaunomycin,peplomycin, pilatin, pirarubicin, porothramycin, pyrindanycin A, TobishiRA-I, rapamycin, rhizoxin, rodorubicin, sibanomicin, siwenmycin,Sumitomo SM-5887, Snow Brand SN-706, Snow Brand SN-07, sorangicin-A,sparsomycin, SS Pharmaceutical SS-21020, SS Pharmaceutical SS-7313B, SSPharmaceutical SS-9816B, steffimycin B, Taiho 4181-2, talisomycin,Takeda TAN-868A, terpentecin, thrazine, tricrozarin A, Upjohn U-73975,Kyowa Hakko UCN-10028A, Fujisawa WF-3405, Yoshitomi Y-25024 andzorubicin.

[0317] A fourth family of antineoplastic agents which may be used incombination with compounds of the present invention consists of amiscellaneous family of antineoplastic agents, including tubulininteracting agents, topoisomerase II inhibitors, topoisomerase Iinhibitors and hormonal agents, selected from but not limited to thegroup consisting of α-carotene, α-difluoromethyl-arginine, acitretin,Biotec AD-5, Kyorin AHC-52, alstonine, amonafide, amphethinile,amsacrine, Angiostat, ankinomycin, anti-neoplaston A10, antineoplastonA2, antineoplaston A3, antineoplaston A5, antineoplaston AS2-1, HenkelAPD, aphidicolin glycinate, asparaginase, Avarol, baccharin, batracylin,benfluron, benzotript, Ipsen-Beaufour BIM-23015, bisantrene,Bristol-Myers BMY-40481, Vestar boron-10, bromofosfamide, WellcomeBW-502, Wellcome BW-773, caracemide, carmethizole hydrochloride,Ajinomoto CDAF, chlorsulfaquinoxalone, Chemes CHX-2053, Chemex CHX-100,Warner-Lambert CI-921, Warner-Lambert CI-937, Warner-Lambert CI-941,Warner-Lambert CI-958, clanfenur, claviridenone, ICN compound 1259, ICNcompound 4711, Contracan, Yakult Honsha CPT-11, crisnatol, curaderm,cytochalasin B, cytarabine, cytocytin, Merz D-609, DABIS maleate,dacarbazine, datelliptinium, didemnin-B, dihaematoporphyrin ether,dihydrolenperone, dinaline, distamycin, Toyo Pharmar DM-341, ToyoPharmar DM-75, Daiichi Seiyaku DN-9693, docetaxel elliprabin,elliptinium acetate, Tsumura EPMTC, the epothilones, ergotamine,etoposide, etretinate, fenretinide, Fujisawa FR-57704, gallium nitrate,genkwadaphnin, Chugai GLA-43, Glaxo GR-63178, grifolan NMF-5N,hexadecylphosphocholine, Green Cross HO-221, homoharringtonine,hydroxyurea, BTG ICRF-187, ilmofosine, isoglutamine, isotretinoin,Otsuka JI-36, Ramot K-477, Otsuak K-76COONa, Kureha Chemical K-AM, MECTCorp KI-8110, American Cyanamid L-623, leukoregulin, lonidamine,Lundbeck LU-23-112, Lilly LY-186641, NCI (US) MAP, marycin, Merrel DowMDL-27048, Medco MEDR-340, merbarone, merocyanlne derivatives,methylanilinoacridine, Molecular Genetics MGI-136, minactivin,mitonafide, mitoquidone mopidamol, motretinide, Zenyaku Kogyo MST-16,N-(retinoyl)amino acids, Nisshin Flour Milling N-021,N-acylated-dehydroalanines, nafazatrom, Taisho NCU-190, nocodazolederivative, Normosang, NCI NSC-145813, NCI NSC-361456, NCI NSC-604782,NCI NSC-95580, ocreotide, Ono ONO-112, oquizanocine, Akzo Org-10172,paclitaxel, pancratistatin, pazelliptine, Warner-Lambert PD-111707,Warner-Lambert PD-115934, Warner-Lambert PD-131141, Pierre FabrePE-1001, ICRT peptide D, piroxantrone, polyhaematoporphyrin, polypreicacid, Efamol porphyrin, probimane, procarbazine, proglumide, Invitronprotease nexin I, Tobishi RA-700, razoxane, Sapporo Breweries RBS,restrictin-P, retelliptine, retinoic acid, Rhone-Poulenc RP-49532,Rhone-Poulenc RP-56976, SmithKline SK&F-104864, Sumitomo SM-108, KuraraySMANCS, SeaPharm SP-10094, spatol, spirocyclopropane derivatives,spirogermanium, Unimed, SS Pharmaceutical SS-554, strypoldinone,Stypoldione, Suntory SUN 0237, Suntory SUN 2071, superoxide dismutase,Toyama T-506, Toyama T-680, taxol, Teijin TEI-0303, teniposide,thaliblastine, Eastman Kodak TJB-29, tocotrienol, topotecan, Topostin,Teijin TT-82, Kyowa Hakko UCN-01, Kyowa Hakko UCN-1028, ukrain, EastmanKodak USB-006, vinblastine sulfate, vincristine, vindesine,vinestramide, vinorelbine, vintriptol, vinzolidine, withanolides andYamanouchi YM-534.

[0318] Alternatively, the present compounds may also be used inco-therapies with other anti-neoplastic agents, such as acemannan,aclarubicin, aldesleukin, alemtuzumab, alitretinoin, altretamine,amifostine, aminolevulinic acid, amrubicin, amsacrine, anagrelide,anastrozole, ANCER, ancestim, ARGLABIN, arsenic trioxide, BAM 002(Novelos), bexarotene, bicalutamide, broxuridine, capecitabine,celmoleukin, cetrorelix, cladribine, clotrimazole, cytarabine ocfosfate,DA 3030 (Dong-A), daclizumab, denileukin diftitox, deslorelin,dexrazoxane, dilazep, docetaxel, docosanol, doxercalciferol,doxifluridine, doxorubicin, bromocriptine, carmustine, cytarabine,fluorouracil, HIT diclofenac, interferon alfa, daunorubicin,doxorubicin, tretinoin, edelfosine, edrecolomab, eflornithine, emitefur,epirubicin, epoetin beta, etoposide phosphate, exemestane, exisulind,fadrozole, filgrastim, finasteride, fludarabine phosphate, formestane,fotemustine, gallium nitrate, gemcitabine, gemtuzumab zogamicin,gimeracil/oteracil/tegafur combination, glycopine, goserelin,heptaplatin, human chorionic gonadotropin, human fetal alphafetoprotein, ibandronic acid, idarubicin, (imiquimod, interferon alfa,interferon alfa, natural, interferon alfa-2, interferon alfa-2a,interferon alfa-2b, interferon alfa-N1, interferon alfa-n3, interferonalfacon-1, interferon alpha, natural, interferon beta, interferonbeta-1a, interferon beta-1b, interferon gamma, natural interferongamma-1a, interferon gamma-1b, interleukin-1 beta, iobenguane,irinotecan, irsogladine, lanreotide, LC 9018 (Yakult), leflunomide,lenograstim, lentinan sulfate, letrozole, leukocyte alpha interferon,leuprorelin, levamisole+fluorouracil, liarozole, lobaplatin, lonidamine,lovastatin, masoprocol, melarsoprol, metoclopramide, mifepristone,miltefosine, mirimostim, mismatched double stranded RNA, mitoguazone,mitolactol, mitoxantrone, molgramostim, nafarelin, naloxone+pentazocine,nartograstim, nedaplatin, nilutamide, noscapine, novel erythropoiesisstimulating protein, NSC 631570 octreotide, oprelvekin, osaterone,oxaliplatin, paclitaxel, pamidronic acid, pegaspargase, peginterferonalfa-2b, pentosan polysulfate sodium, pentostatin, picibanil,pirarubicin, rabbit antithymocyte polyclonal antibody, polyethyleneglycol interferon alfa-2a, porfimer sodium, raloxifene, raltitrexed,rasburicase, rhenium Re 186 etidronate, RII retinamide, rituximab,romurtide, samarium (153 Sm) lexidronam, sargramostim, sizofiran,sobuzoxane, sonermin, strontium-89 chloride, suramin, tasonermin,tazarotene, tegafur, temoporfin, temozolomide, teniposide,tetrachlorodecaoxide, thalidomide, thymalfasin, thyrotropin alfa,topotecan, toremifene, tositumomab-iodine 131, trastuzumab, treosulfan,tretinoin, trilostane, trimetrexate, triptorelin, tumor necrosis factoralpha, natural, ubenimex, bladder cancer vaccine, Maruyama vaccine,melanoma lysate vaccine, valrubicin, verteporfin, vinorelbine,VIRULIZIN, zinostatin stimalamer, or zoledronic acid; abarelix; AE 941(Aeterna), ambamustine, antisense oligonucleotide, bcl-2 (Genta), APC8015 (Dendreon), cetuximab, decitabine, dexaminoglutethimide,diaziquone, EL 532 (Elan), EM 800 (Endorecherche), eniluracil,etanidazole, fenretinide, filgrastim SD01 (Amgen), fulvestrant,galocitabine, gastrin 17 immunogen, HLA-B7 gene therapy (Vical),granulocyte macrophage colony stimulating factor, histaminedihydrochloride, ibritumomab tiuxetan, ilomastat, IM 862 (Cytran),interleukin-2, iproxifene, LDI 200 (Milkhaus), leridistim, lintuzumab,CA 125 MAb (Biomira), cancer MAb (Japan Pharmaceutical Development),HER-2 and Fc MAb (Medarex), idiotypic 105AD7 MAb (CRC Technology),idiotypic CEA MAb (Trilex), LYM-1-iodine 131 MAb (Techniclone),polymorphic epithelial mucinyttrium 90 MAb (Antisoma), marimastat,menogaril, mitumomab, motexafin gadolinium, MX 6 (Galderma), nelarabine,nolatrexed, P 30 protein, pegvisomant, pemetrexed, porfiromycin,prinomastat, RL 0903 (Shire), rubitecan, satraplatin, sodiumphenylacetate, sparfosic acid, SRL 172 (SR Pharma), SU 5416 (SUGEN), TA077 (Tanabe), tetrathiomolybdate, thaliblastine, thrombopoietin, tinethyl etiopurpurin, tirapazamine, cancer vaccine (Biomira), melanomavaccine (New York University), melanoma vaccine (Sloan KetteringInstitute), melanoma oncolysate vaccine (New York Medical College),viral melanoma cell lysates vaccine (Royal Newcastle Hospital), orvalspodar.

[0319] Alternatively, the present compounds may also be used inco-therapies with other anti-neoplastic agents, such as other kinaseinhibitors including p38 inhibitors and CDK inhibitors, TNF inhibitors,metallomatrix proteases inhibitors (MMP), COX-2 inhibitors includingcelecoxib, rofecoxib, parecoxib, valdecoxib, and etoricoxib, NSAID's,SOD mimics or α_(v)β₃ inhibitors.

[0320] The present invention comprises processes for the preparation ofa compound of Formulas I-IV.

[0321] Also included in the family of compounds of Formulas I-IV are thepharmaceutically-acceptable salts thereof. The term“pharmaceutically-acceptable salts” embraces salts commonly used to formalkali metal salts and to form addition salts of free acids or freebases. The nature of the salt is not critical, provided that it ispharmaceutically-acceptable. Suitable pharmaceutically-acceptable acidaddition salts of compounds of Formulas I-IV may be prepared from aninorganic acid or from an organic acid. Examples of such inorganic acidsare hydrochloric, hydrobromic, hydroiodic, nitric, carbonic, sulfuricand phosphoric acid. Appropriate organic acids may be selected fromaliphatic, cycloaliphatic, aromatic, arylaliphatic, heterocyclic,carboxylic and sulfonic classes of organic acids, example of which areformic, acetic, adipic, butyric, propionic, succinic, glycolic,gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic,fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, mesylic,4-hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic),methanesulfonic, ethanesulfonic, ethanedisulfonic, benzenesulfonic,pantothenic, 2-hydroxyethanesulfonic, toluenesulfonic, sulfanilic,cyclohexylaminosulfonic, camphoric, camphorsulfonic, digluconic,cyclopentanepropionic, dodecylsulfonic, glucoheptanoic,glycerophosphonic, heptanoic, hexanoic, 2-hydroxy-ethanesulfonic,nicotinic, 2-naphthalenesulfonic, oxalic, palmoic, pectinic,persulfuric, 2-phenylpropionic, picric, pivalic propionic, succinic,tartaric, thiocyanic, mesylic, undecanoic, stearic, algenic,β-hydroxybutyric, salicylic, galactaric and galacturonic acid. Suitablepharmaceutically-acceptable base addition salts of compounds of FormulasI-IV include metallic salts, such as salts made from aluminum, calcium,lithium, magnesium, potassium, sodium and zinc, or salts made fromorganic bases including primary, secondary and tertiary amines,substituted amines including cyclic amines, such as caffeine, arginine,diethylamine, N-ethyl piperidine, aistidine, glucamine, isopropylamine,lysine, morpholine, N-ethyl morpholine, piperazine, piperidine,triethylamine, trimethylamine. All of these salts may be prepared byconventional means from the corresponding compound of the invention byreacting, for example, the appropriate acid or base with the compound ofFormulas I-IV

[0322] Also, the basic nitrogen-containing groups can be quaternizedwith such agents as lower alkyl halides, such as methyl, ethyl, propyl,and butyl chloride, bromides and iodides; dialkyl sulfates likedimethyl, diethyl, dibutyl, and diamyl sulfates, long chain halides suchas decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides,aralkyl halides like benzyl and phenethyl bromides, and others. Water oroil-soluble or dispersible products are thereby obtained.

[0323] Examples of acids that may be employed to form pharmaceuticallyacceptable acid addition salts include such inorganic acids ashydrochloric acid, sulphuric acid and phosphoric acid and such organicacids as oxalic acid, maleic acid, succinic acid and citric acid. Otherexamples include salts with alkali metals or alkaline earth metals, suchas sodium, potassium, calcium or magnesium or with organic bases.Preferred salts include hydrochloride, phosphate and edisylate.

[0324] Additional examples of such salts can be found in Berge et al.,J. Pharm. Sci., 66, 1 (1977).

General Synthetic Procedures

[0325] The compounds of the invention can be synthesized according tothe following procedures of Schemes 1-43, wherein the substituents areas defined for Formulas I-IV, above, except where further noted.

[0326] Cyclic amides can be prepared according to the method set out inScheme 1. The amino group of compound 1 (where R^(o) is alkyl, aryl, andthe like) is protected, such as with Boc anhydride, followed bytreatment, to remove the ester, such as with base, forming the protectedamine/free acid 2. Alternatively, other amino protecting groups known inthe art can be used. Substitued amines are coupled with the free acid,such as with EDC, to form the protected amine/amide 3. The protectedamine moiety is removed, such as with acid, and reacted via one stepreductive alkylation with carbonyl-containing compounds to form the1-amido-2-substituted amino-compounds 4. Preferably the amination is inan alcohol, such as MeOH, EtOH or propanol, and at a temperature betweenabout 0-50° C., such as RT. Aldehydes or ketones are preferredcarbonyl-containing compounds. Alternative carbonyl-containing compoundsare, for example, bisulfite adducts or semiacetals, acetals, semiketalsor ketals of compounds with alcohols, for example lower hydroxyalkylcompounds; or thioacetals or thioketals of compounds with mercaptans,for example lower alkylthio compounds. The reductive alkylation ispreferably carried out with hydrogenation in the presence of a catalyst,such as platinum or especially palladium, which is preferably bonded toa carrier material, such as carbon, or a heavy metal catalyst, such asRaney nickel, at normal pressure or at pressures of from 0.1 to 10MegaPascal (MPa), or with reduction by means of complex hydrides, suchas borohydrides, especially alkali metal cyanoborohydrides, for examplesodium cyanoborohydride, in the presence of a suitable acid, preferablyrelatively weak acids, such as lower alkylcarboxylic acids, especiallyacetic acid, or a sulfonic acid, such as p-toluenesulfonic acid; incustomary solvents, for example alcohols, such as methanol or ethanol,or ethers, for example cyclic ethers, such as tetrahydrofuran, in thepresence or absence of water.

[0327] Alternatively, compounds 4 can be prepared from mixed acid/amines5 as shown in Scheme 2. Substituted amines are coupled with the mixedacid/amines 5 such as with a coupling reagent, for example EDC, to formthe mixed amine/amide 6. Substituted carbonyl compounds, such as acidhalides, anhydrides, carboxylic acids, esters, ketones, aldehydes andthe like, are added to the mixed amine/amide 6 followed with reductionto give the substituted amide/substituted amine compounds 4.

[0328] Imino compounds 7 can be formed from the mixed amine/amides 6,such as by reacting with a substituted carbonyl compound.

[0329] Substituted cyclic carboxamides can be prepared from thecorresponding imino analogs by the process outlined in Scheme 4.Treatment of the imino compound 7 with a reducing agent yields compound4. Reagents which can be used to add hydrogen to an imine double bondinclude borane in THF, LiAlH₄, NaBH₄, sodium in EtOH and hydrogen in thepresence of a catalyst, among others.

[0330] Substituted carboxamides 4 can be prepared from the correspondinghalo analogs 8 by the process outlined in Schemne 5. Substituted aminoacids 9 are prepared from the corresponding chioro compounds 8 such asby reacting with an amine at a suitable temperature, such as about 80°C. The acid 9 is coupled with an amine, preferably in the presence of acoupling agent such as EDC, to form the corresponding amide 4.

[0331] The amination process can be carried out as an Ullmann typereaction using a copper catalyst, such as copper[0] or a copper[I]compound such as copper[I]oxide, copper[I]bromide or copper[I]iodide inthe presence of a suitable base (such as a metal carbonate, for exampleK₂CO₃) to neutralize the acid generated in the reaction. This reactionis reviewed in Houben-Weyl “Methoden der Organischen Chemie”, Band 11/1,page 32-33, 1958, in Organic Reactions, 14, page 19-24, 1965 and by J.Lindley (1984) in Tetrahedron, 40, page 1433-1456. The amount ofcatalyst is typically in the range of 1 to 20 mole percent. The reactionis carried out in an inert, aprotic solvent such as an ether (forexample dimethoxyethane or dioxane) or an amide (for exampledimethylformamide or N-methylpyrrolidone), under an inert atmosphere inthe temperature range of 60-180° C.

[0332] An alternative amination process involves using a Group VIIIelement, where the metal core of the catalyst should be a zero-valenttransition metal, such as palladium or nickel, which has the ability toundergo oxidative addition to the aryl-halogen bond. The zero valentstate of the metal may be generated in situ from the M[II] state. Thecatalyst complexes may include chelating ligands, such as alkyl, aryl orheteroaryl derivatives of phosphines or biphosphines, imines or arsines.Preferred catalysts contain palladium or nickel. Examples of suchcatalysts include palladium[II]chloride, palladium[II]acetate,tetrakis(triphenyl-phosphine)palladium[0] and nickel[II]acetylacetonate.The metal catalyst is typically in the range of 0.1 to 10 mole percent.The chelating ligands may be either monodentate, as in the case forexample of trialkyphosphines, such as tributylphosphine,triarylphosphines, such as tri-(ortho-tolyl)phosphine, and triheteroarylphosphines, such as tri-2-furylphosphine; or they may be bidentate suchas in the case of 2,2′-bis(diphenylphosphino)-1,1′binaphthyl,1,2-bis(diphenylphosphino)ethane, 1,1′-bis(diphenylphosphino)ferroceneand 1-(N,N-dimethyl-amino)-1′-(dicyclohexylphosphino)biphenyl. Thesupporting ligand may be complexed to the metal center in the form of ametal complex prior to being added to the reaction mixture or may beadded to the reaction mixture as a separate compound. The supportingligand is typically present in the range 0.01 to 20 mole percent. It isoften necessary to add a suitable base to the reaction mixture, such asa trialkylamine (for example DIEA or1,5-diazabicyclo[5,4,O]undec-5-ene), a Group I alkali metal alkoxide(for example potassium tert-butoxide) or carbonate (for example cesiumcarbonate) or potassium phosphate. The reaction is typically carried outin an inert aprotic solvent such as an ether (for exampledimethoxyethane or dioxane) or an amide (for example DMF orN-methylpyrrolidone), under an inert atmosphere in the temperature rangeof 60-180° C.

[0333] The amination is preferably carried out in an inert, aprotic,preferably anhydrous, solvent or solvent mixture, for example in acarboxylic acid amide, for example dimethylformamide ordimethylacetamide, a cyclic ether, for example THF or dioxane, or anitrile, for example CH₃CN, or in a mixture thereof, at an appropriatetemperature, for example in a temperature range of from about 40° C. toabout 180° C., and if necessary under an inert gas atmosphere, forexample a nitrogen or argon atmosphere.

[0334] Substituted carboxamides 4 can be prepared from the correspondinghalo analogs 8 by the process outlined in Scheme 6. The chloro acid 8 iscoupled with an amine, preferably in the presence of a coupling agentsuch as EDC, to form the corresponding chloro amide 10. Substitutedamino-amides 4 are prepared from the corresponding chloro compounds 10such as by reacting with an amine at a suitable temperature, such asabout 80° C. The amination reaction can be run in the presence of anappropriate catalyst such as a palladium catalyst, in the presence of anaprotic base such as sodium t-butoxide or cesium carbonate, or a nickelcatalyst, or a copper catalyst.

[0335] Substituted carboxamides 4 can be prepared from the correspondingbromo/chloro analogs 11 by the process outlined in Scheme 7. Thebromo/chloro acid 11 is coupled with an amine, preferably in thepresence of a coupling agent such as EDC, to form the correspondingbromo substituted amide 12. Suzuki coupling with the bromo amide 12 andsuitable boronic acids provides the substituted amide 10. Substitutedamino-amides 4 are prepared from the corresponding chloro compounds 10as described in Scheme 6.

[0336] Substituted pyridines can be prepared such as by the method foundin Scheme 8. 2-Aminonicotinic acid 13 is coupled with a substitutedamine at a suitable temperature, nonprotic solvent such as CH₂Cl₂, suchas with EDC and HOBt, to form the nicotinamide 14. The nicotinamide 14is reductively alkylated such as with substituted 4-benzaldehydes andNaBH(OAc)₃, to yield the 2-substituted amino-pyridyl carboxamides 15.

[0337] Substituted pyridines may be prepared by the method found inScheme 9. 2-Chloro-nicotinic acid 16 (where LG is OH) is coupled with anamine at a suitable temperature, such as a temperature over about 100°C. to give the 2-substituted amino-nicotinic acid 17. The 2-substitutedamino-nicotinic acid 17 is reacted with a substituted amine in thepresence of a coupling reagent, such as BOP-Cl and base, such as TEA toform the 2-substituted amino-nicotinamide 15.

[0338] Alternatively, 2-chloro-nicotinoyl chloride (LG is Cl) is coupledfirst with R²-NH₂, such as in the presence of base, e.g., NaHCO₃, in asuitable solvent, such as CH₂Cl₂, to form the amide 16A, then coupledwith a benzylamine to yield the 2-substituted amino-nicotinamide 15.

[0339] Imino-substituted pyridines may be prepared by the method foundin Scheme 10. (2-Amino-(4-pyridyl))-carboxamide 18 is reacted withsubstituted 4-benzaldehydes, such as in the presence ofp-toluenesulfonic acid monohydrate to yield the imino compound 19.

[0340] Substituted pyridines alternatively may be prepared by the methodfound in Scheme 11. The imino compound 19 is reduced, such as withNaBH₄, to form the substituted amine 20.

[0341] Substituted pyridines can be prepared by the process outlined inScheme 12. A solution of sodium hypobromite is freshly prepared andadded to 2-hydroxynicotinic acid 21 and heated, preferably at atemperature at about 50° C. Additional hypobromite solution may beneeded to form the bromo compound 22. The 5-bromo-2-hydroxynicotinicacid 22 is reacted with thionyl chloride, preferably at atemperature >RT, more preferably at about 80° C. to form the2-chloro-nicotinic acid analog 23. The acid is coupled with an amine,preferably in the presence of EDC, HOBT, and DIEA to form thecorresponding substituted amide 24. Suzuki coupling with the bromo amideand suitable boronic acids, provides the substituted nicotinamide 25.2-Amino-nicotinamides 26 are prepared from the corresponding chlorocompounds 25 such as by reacting with substituted amines at a suitabletemperature, such as about 80° C.

[0342] Alternatively, sulfonamides 27 can be prepared from amines 6 asshown in Scheme 13. Substituted sulfonyl compounds, such as sulfonylhalides, preferably chloro or bromo, sulfonic acids, an activated esteror reactive anhydride, or in the form of a cyclic amide, and the like,are added to the amine 6 to give the sulfonamide compounds 27.

[0343] The reaction is carried out in a suitable solvent, such asCH₂Cl₂, at a temperature between about RT to about the refluxtemperature of the solvent, in the presence of a suitable base, such asDIEA or DMAP.

[0344] The amino group of compounds 6 is preferably in free form,especially when the sulfonyl group reacting therewith is present inreactive form. The amino group may, however, itself be a derivative, forexample by reaction with a phosphite, such as diethylchlorophosphite,1,2-phenylene chlorophosphite, ethyldichlorophosphite, ethylenechlorophosphite or tetraethylpyrophosphite. A derivative of such acompound having an amino group also can be a carbamic acid halide or anisocyanate.

[0345] The condensation of activated sulfonic esters, reactiveanhydrides or reactive cyclic amides with the corresponding amines iscustomarily carried out in the presence of an inorganic base, such as analkaline metal hydrogen carbonate of carbonate, or especially an organicbase, for example simple lower (alkyl)₃-amines, for example TEA ortributylamine, or one of the above-mentioned organic bases. If desired,a condensation agent is additionally used, for example as described forfree carboxylic acids.

[0346] The condensation is preferably carried out in an inert, aprotic,preferably anhydrous, solvent or solvent mixture, for example in acarboxylic acid amide, for example formamide or DMF, a halogenatedhydrocarbon, for example CH₂Cl₂, CCl₄ or chlorobenzene, a ketone, forexample acetone, a cyclic ether, for example THF or dioxane, an ester,for example EtOAc, or a nitrile, for example CH₃CN, or in a mixturethereof, as appropriate at reduced or elevated temperature, for examplein a temperature range of from about −40° C. to about 100° C.,preferably from about −10° C. to about 70° C., and when arylsulfonylesters are used also at temperatures of from about 10-30° C., and ifnecessary under an inert gas atmosphere, for example a nitrogen or argonatmosphere.

[0347] Alcoholic solvents, for example EtOH, or aromatic solvents, forexample benzene or toluene, may also be used. When alkali metalhydroxides are present as bases, acetone may also be added whereappropriate.

[0348] Substituted pyridines can be prepared by the process outlined inScheme 14. 2-Chloronicotinic acid 28 and substituted amine are coupledunder conditions similar to that described in the previous schemes togive the amide 29. 6-Chloro-2-aminopyridines 30 are prepared from theamide 29, such as by reacting with substituted amines at a suitabletemperature, such as above about 80° C., preferably above about 100° C.,more preferably at about 130° C., neat. 6-Chloro-2-aminopyridines 30 arede-chlorinated such as by hydrogenation, for example by treatment withH₂ in the presence of Pd/C, to yield other compounds of the presentinvention 31.

[0349] 1,2,3,6-Tetrahydro-pyridyl substituted anilines (where R^(x) is asubstituent selected from those available for substituted R²) areprepared such as by the procedure described in Scheme 15. Nitrobenzenes32 are brominated, such as with bromine in the presence of acid, H₂SO₄for example, or with NBS to yield the 3-bromo derivative 33. Suzukicoupling of the bromo-derivative 33 and a substituted pyridylboronicacid, such as at a temperature above RT, preferably above about 50° C.,and more preferably at about 80° C., yields the pyridyl derivative 34.Alkylation of the nitrophenyl-pyridine 34, such as by treatment withiodomethane, preferably above about 50° C., and more preferably at about80° C., yields the pyridinium compound 35, which upon reduction, such asby NaBH₄, yields the tetrahydyropyridine 36.

[0350] 6-Amino substituted pyridines are prepared such as by theprocedure described in Scheme 16. Similar to the method of Scheme 13,chloropyridine 37 and is reacted with an amine, preferably above about50° C., and more preferably at about 80° C., to yield the6-aminopyridines 38.

[0351] A series of substituted anilines are prepared such as by theprocedure described in Scheme 17. A nitrobenzyl bromide 39 is coupledwith morpholine, such as at a temperature at about RT, to yield theheterocyclylmethyl nitrobenzene derivative. Reduction of the nitrocompound, such as with iron powder, preferably above about 50° C., andmore preferably at about 80° C., yields the heterocyclylmethylsubstituted aniline 40.

[0352] Protected alkylamine substituted anilines can be prepared fromthe nitro free amines 41, such as with standard protecting agents andchemistry known in the art, such as BOC chemistry. Reduction of theprotected nitro compound, such as with iron powder, preferably aboveabout 50° C., and more preferably at about 80° C., yields the aniline42.

[0353] Sulfonamide substituted anilines can be prepared fromnitrobenzenesulfonyl chlorides 43. Coupling of nitrobenzenesulfonylchlorides 43 with reactive heterocyclic compounds, such as substitutedpiperazines, piperidines, and the like, in a protic solvent such asEtOH, such as at a temperature about RT, yields thenitrobenzenesulfonamides 43. Reduction of the nitro benzenesulfonamide,such as with iron powder, preferably above about 50° C., and morepreferably at about 80° C., yields the aniline 44.

[0354] A series of perhaloalkyl-substituted anilines 47, where R^(y)represents perhaloalkyl radicals, are prepared such as by the proceduredescribed in Scheme 18. 1-Nitro-4-(perfluoroethyl)benzene can besynthesized by the method described in the reference [John N. Freskos,Synthetic Communications, 18(9), 965-972 (1988)]. Alternatively,1-Nitro-4-(perfluoroalkyl)benzene can be synthesized from the nitrocompound, where LG is a leaving group, such as iodo, by the methoddescribed by W. A. Gregory, et al. [J. Med. Chem., 1990, 33, 2569-2578].

[0355] Reduction of the nitrobenzenes 46, such as with iron powder, at atemperature above about 50° C., and preferably at about 80° C., yieldsthe aniline 47. Hydrogenation, such as with H₂ atmosphere in thepresence of catalyst, such as 10% Pd/C, is also possible.

[0356] Additional series of substituted anilines (where R^(x) is asubstituent selected those available for substituted R²)—are preparedsuch as by the procedures described in Scheme 19. 2-Alkoxy substitutedanilines 50 are prepared from the corresponding phenol compounds 48 suchas by the Mitsunobu reaction, including treatment with aN,N-dialkylethanolamine and PPh₃ and DEAD to give the correspondingnitro compound 49, followed by hydrogenation, such as with H₂ to givethe aniline 50.

[0357] Alternatively, piperazinyl substituted anilines 53 can beprepared by the treatment of an aniline 51 with anN-substituted-bis(2-chloroethyl)amine, base, such as K₂CO₃ and NaI, at atemperature above about 50° C., preferably above about 100° C., and morepreferably at about 170° C., to give the piperazinylbenzene compound 52.Nitration, such as with H₂SO₄ and KNO₃, at a temperature above 0° C.,and preferably at about RT, followed by hydrogenation, such as with H₂atmosphere gives the substituted aniline 53.

[0358] Alternatively, piperazinyl substituted anilines 56 can beprepared by the treatment of a fluoro-nitro-substituted aryl compounds54. The fluoro-nitro-substituted aryl compounds 54 and 1-substitutedpiperazines are heated, preferably neat, at a temperature above about50° C., and preferably at about 90° C., to yield thepiperazinyl-nitroaryl compounds 55. Hydrogenation, such as with H₂atmosphere in the presence of a catalyst, such as 10% Pd/C, gives thesubstituted aniline 56.

[0359] Substituted indolines are prepared such as by the proceduresdescribed in Scheme 20. Substituted amino-indolines 59 are prepared fromthe nitroindoline 57 and a ketone in the presence of NaHB(OAc)₃ to formthe 1-substituted indoline 58. The nitroindoline 58 is hydrogenated,such as with H₂ in the presence of a catalyst, such as Pd/C, to yieldthe amino-indoline 59.

[0360] Alternatively, substituted amino-indolines 62 are prepared fromthe nitroindoline 57. Nitroindoline 57, is reacted with an acid chlorideto form an amide. Further treatment with a primary or secondary amine,preferably a secondary amine, such as in the presence of NaI, at atemperature above about 50° C., and preferably at about 70° C. yieldsthe nitroindoline 60. The nitro compound 60 is hydrogenated, such aswith H₂ in the presence of a catalyst, such as Pd/C, to yield theamino-indoline 61. The carbonyl is reduced, such as with BH₃-THF, toyield 1-aminoalkyl-indolines 62.

[0361] Substituted indolines are prepared such as by the proceduresdescribed in Scheme 21. Substituted acetamides 64 are prepared from thecoupling of halo-5-nitroanilines 63 (where LG is bromo or chloro,preferably chloro) and an acylating agent, such as acetyl chloride oracetic anhydride, under standard coupling chemistry, such as with DIEA,and DMAP, at a temperature of about RT, in a suitable solvent, such asCH₂Cl₂, DMF and/or DMAC. The N-(2-methylprop-2-enyl)acetamide 65 isprepared from the acetamide 64, such as by the treatment of base, suchas NaH in a suitable solvent such as NMP or anhydrous DMF and a3-halo-2-methylpropene such as 3-bromo-2-methylpropene or3-chloro-2-methylpropene, at a temperature between about 0° C. and RT,and preferably at about RT; or with CsCO₃ at a temperature above RT,preferably above about 50° C. and more preferably above about 60° C.Cyclization of the N-(2-methylprop-2-enyl)acetamide 65, such as by theHeck-type reaction (treatment with Pd(OAc)₂ in the presence of base, forexample tetraethyl-arrmonium chloride, sodium formate, and NaOAc) at atemperature above about 50° C., and preferably at about 80° C., yieldsthe protected (3,3-dimethyl-2,3-dihydro-indol-1-yl)ethanone 66.Deprotection, such as with strong acid such as AcOH, or HCl at atemperature above about 50° C., and preferably at about 70-80° C.,yields the 3,3-dimethyl-6-nitro-2,3-dihydro-indol-1-yl 67.Alternatively, the protected dihydro-6-nitro indoline 66 can be reduced,such as with Fe, or with 10% Pd/C in the presence of an excess ofNH₄CO₂H, or with H₂ in the presence of a catalyst to form the protecteddihydro-6-amino indoline 66a.

[0362] Substituted anilines are prepared such as by the proceduresdescribed in Scheme 22. Nitrophenyl esters 69 are formed from the acid68, such as by treatment with MeOH and acid. Alkylation of the ester 69,such as by treatment with base, such as Nail, followed by alkyl halide,yields the branched alkyl compounds 70. Reduction of the ester 70, suchas with BH₃, yields the alcohol 71. The aldehyde 72 is prepared from thealcohol 71, such as by treatment with TPAP in the presence ofN-methylmorpholine-N-oxide. Subsequent treatment withmethoxymethyltriphenylphosphonium chloride and KHMDS yields 72. Couplingof the aldehyde 72 with morpholine, such as with NaBH(OAc)₃ yields thetertiary amine 73. Reduction of the nitro compound, such as with acid,for example AcOH, and zinc yields the aniline 74.

[0363] Substituted aniline compounds (where R^(x) is a substituentselected those available for substituted R², preferably haloalkyl andalkyl) are prepared such as by the procedure described in Scheme 23.Alkynyl-aniline 81, prepared similar to that described in Scheme 23, ishydrogenated such as with H₂ in the presence of a catalyst, such asPd(OH)₂, to yield the substituted alkyl 82.

[0364] Substituted bromophenyl compounds are prepared such as by theprocedure described in Scheme 24. Bromine is added to a optionallysubstituted nitrobenzene 83, AgSO₄ and acid, such as H₂SO₄, to providethe bromo derivative 84.

[0365] Substituted anilines are prepared such as by the proceduredescribed in Scheme 25 (where R^(t) and R^(v) are alkyl, or togetherwith the nitrogen atom form a 4-6 membered heterocyclic ring). Acryloylchloride 85 is reacted with an amine, preferably a secondary amine, suchas at a temperature between about 0° C. and about RT, to form the amide86. A bromo-nitrobenzene 84 is reacted with the amide 88, such as in thepresence of base, for example TEA, together with Pd(OAc)₂ and Pd(PPh₃)₄,at a temperature above about 50° C., and preferably at about 120° C.,such as in a sealed container, to form the substituted alkene 87.Hydrogenation of the alkene 87, such as with H₂ in the presence of acatalyst, for example Pd/C catalyst yields the substituted aniline 88.Reduction of the amide 88, such as with LiALH₄, at a temperature aboveabout 50° C., and preferably at about 80° C. yields the aniline 89.

[0366] Substituted indoles are prepared such as by the proceduredescribed in Scheme 26. A nitroindole 90 is coupled with a halocompound, in the presence of base, for example K₂CO₃. Heating at atemperature above about 50° C., and preferably at about reflux yieldsthe substituted-nitro-1H-indole 91. Hydrogenation similar to conditionsdescribed above yieldS the amino derivative 92.

[0367] Substituted pyrimidines are prepared such as by the proceduredescribed in Scheme 27. 2-Methylthio-5-pyrimidyl acids 95 are preparedfrom the corresponding esters 93 similar to procedures described above.The amides 96 are formed from the acids 95 by coupling with the aminesuch as in the presence of HATU and base, TEA for example. Themethylthio group can be removed, such as with Raney-Ni and heat,preferably at about reflux temperature, to form the pyrimidine 97.

[0368] Substituted anilines are prepared such as by the proceduredescribed in Scheme 28. Treatment with the haloalkyl alcohol 101 with analcohol, such as in the presence of DEAD and PPh₃ yields the ether 102or 103.

[0369] Functionalized pyridines are prepared such as by the proceduredescribed in Scheme 29. 2-Fluoropyridine 104 is treated with base, suchas LDA, at a temperature below about 0° C., and preferably at about −78°C., and quenched with a stream of dry CO₂ to form the nicotinic acid105. Alternatively, solid CO₂ (dry ice) can be used, preferably driedwith N₂ prior to use. The acid 105 is converted to the acid halide 106,such as by treatment with thionyl chloride and heating at a temperatureabove about 50° C., and preferably at about reflux.

[0370] Chloro-substituted pyridines 107 are prepared such as by theprocedure described in Scheme 30. 2-Chloronicotinic acid is activatedwith ethyl chloroformate, in the presence of base, such as TEA, at atemperature of about RT. Reaction with an amine produces amide 107.Alternatively, the amine can be coupled with the acid chloride 108, suchas with polymer-supported DIEA. Excess acid chloride is removed bytreating the reaction mixture with polymer-supported trisamine resin, toform amide 107.

[0371] Amino-substituted indoles 111 are prepared such as by theprocedure described in Scheme 31. Nitroindoline 109 is reacted withN-methyl-4-piperidone in the presence of NaOMe at a temperature aboveabout 50° C., and preferably at about reflux, to form the 3-substitutedindole 110. Hydrogenation as previously discussed yields the aminoindole 111.

[0372] Alkylated indazoles can be prepared by the process outlined inScheme 32. To a solution of 6-nitroindazole 112 in a solvent such as THFis added strong base, such as NaH at a temperature below RT, preferablyat about 0° C. Alkylhalides, such as where R″ is methyl, are added andreacted at a temperature about RT to give 1-alkyl-6-nitro-1H-indazole113. The nitro indazole 113 is hydrogenated, such as with an H₂atmosphere in the presence of a catalyst, such as Pd/C to give the1-substituted-6-amino-1-indazole 114.

[0373] Brominated indazoles can be prepared by the process outlined inScheme 33. NBS is slowly added to an acidic solution, such as a mixtureof TFA:H₂SO₄ (5:1) and tert-butyl-4-nitrobenzene 115 at a temperature ofabout RT to yield the brominated compound 116.

[0374] Substituted anilines (where R^(x) is a substituent selected thoseavailable for substituted R²) can be prepared by the process outlined inScheme 34. A mixture of 1-(substituted)-2-bromo-4-nitrobenzene 117 andN-methylpiperazine is heated, such as with or without solvent,preferably without solvent, at a temperature above RT, preferably at atemperature above about 100° C., and more preferably at a temperature atabout 130° C. to give the1-[5-(substituted)-2-nitrophenyl]-4-methylpiperazine 118. The nitrocompound 118 is hydrogenated, such as with an H₂ atmosphere in thepresence of a catalyst, such as Pd/C to furnish4-(substituted)-2-(4-methylpiperazinyl)phenylamine 119.

[0375] Tricyclic heterocycles can be prepared by the process outlined inScheme 35. 7-Nitro-2,3,4-trihydroisoquinolin-1-one 120 is heated inPOC1₃ at a temperature above RT, preferably at a temperature sufficientfor reflux, to form the 1-chloro-7-nitro-3,4-dihydroisoquinoline 121.The 1-chloro-7-nitro-3,4-dihydroisoquinoline 121 is dissolved in asolvent, such as THF, and H₂NNH₂ is added. The reaction is heated withHC(OEt)₃ at a temperature above RT, preferably at a temperature aboveabout 75° C., and more preferably at a temperature at about 115° C. togive the nitro-substituted tricyclic. Hydrogenation, such as with an H₂atmosphere in the presence of a catalyst, such as Pd/C, gives2-amino-5,6,7-trihydro-1,2,4-triazolo[3,4-a]isoquinoline 122.

[0376] Indolinyl substituted carboxamides can be prepared from thecorresponding nitro indoline 123 by the process outlined in Scheme 36.For example, 3,3-dimethyl-6-nitroindoline 123 is alkylated, such as withN-protected-4-formylpiperidine in the presence of NaHB(OAc)₃ and acid,such as glacial AcOH, and solvent, such as dichloromethane, at atemperature of about RT, to afford the alkylated indane 124.Hydrogenation of the alkylated indane 124, such as with an H₂ atmospherein the presence of a catalyst, such as Pd/C, in the presence of asolvent, such as an alcohol, preferably MeOH, to give the aminointermediate 125. Alternatively, other hydrogenation methods can beused, such as Fe powder with NH₄Cl. Coupling of the amine 125, such aswith 2-chloronicotinic acid and DIEA, HOBt and EDC, in a solvent such asCH₂Cl₂ at a temperature of about RT provides the protected carboxamide126, which upon deprotection and alkylation yields other compounds ofthe invention, 127 and 128, respectively. Alternatively, amine 125 isreacted with 2-fluoronicotinoyl chloride to form a 2-fluoronicotinamide,which can be alkylated, such as in Scheme 10.

[0377] Substituted anilines can be prepared by the process outlined inScheme 37 (where R^(x) is a substituent selected those available forsubstituted R², preferably haloalkyl and alkyl). 1-Methyl-4-piperidinone129 is added to a solution of strong base such as LiHMDS, in a solventsuch as THF, at a temperature below RT, preferably lower than about −50°C., more preferably at about −78° C. Tf₂NPh is reacted with the enolateat a temperature of about RT, to givel-methyl-4-(1,2,5,6-tetrahydro)pyridyl-(trifluoromethyl)sulfonate. Amixture of the triflate intermediate, bis(pinacolato)diboron, potassiumacetate, PdCl₂dppf, and dppf in a solvent such as dioxane is heated at atemperature above RT, preferably at a temperature above about 50° C.,and more preferably at a temperature at about 80° C. to give4,4,5,5-tetramethyl-2-(1-methyl(4-1,2,5,6-tetrahydropyridyl))-1,3,2-dioxaborolane130. The substituted aniline 131 is formed from the 1,3,2-dioxaborolane130 such as with treatment with an amine in the presence of PdCl₂dppfand base, such as K₂CO₃, in a solvent such as DMF at a temperature aboveRT, preferably at a temperature above about 50° C., and more preferablyat a temperature at about 80° C.

[0378] Substituted anilines can be prepared by the process outlined inScheme 38. 4-Cyano-4-phenylpiperidine hydrochloride 132 is treated withbase, such as KOH, at a temperature above RT, preferably at atemperature above about 100° C., and more preferably at a temperature atabout 160° C., to provide the phenyl piperidine 133. Alkylation of thephenyl piperidine 133, such as with formaldehyde and NaCNBH₃ in asolvent such as CH₃CN, with sufficient acid to maintain the reaction pHnear 7, to provide the alkylated piperidine 134. Nitration of thephenylpiperidine 134, such as with H₂SO₄ and fuming HNO₃ at atemperature below RT, and preferably at about 0° C., gives the nitrointermediate 135. Hydrogenation of the nitro intermediate 135, such aswith an H2 atmosphere in the presence of a catalyst, such as Pd/C., inthe presence of a solvent, such as an alcohol, preferably MeOH, to givethe amino intermediate 136.

[0379] Substituted amides can be prepared by the process outlined inScheme 39. 3-Nitrocinnamic acid 137 is coupled with 1-methylpiperazinein the presence of EDC and a solvent such as CH₂Cl₂, at a temperature ofabout RT gives the carboxamide 138.

[0380] Substituted benzylamines can be prepared by the process outlinedin Scheme 40. A substituted bromobenzylamine 139 where R^(2a) is asubstituent described for R² is protected such as with Boc₂O in thepresence of base, such as TEA in an appropriate solvent such as CH₂Cl₂.The protected bromobenzylamine 140 is alkylated, such as with1-dimethylamino-2-propyne in the presence of catalyst, such asPdCl₂(PPh₃)₂ bis(triphenyphosphino)-palladium chloride, and CuI, in thepresence of base, such as TEA, at a temperature above RT, preferably ata temperature above about 50° C., and more preferably at a temperatureat about 100° C., such as in a sealed tube, to form thepropynylbenzylamine 141. The propynylbenzylamine is hydrogenated such aswith H₂ in the presence of Pd(OH)₂ and MeOH to provide thepropylbenzylamine 142. Deprotection, such as with strong acid, such asTFA, for removal of a Boc protecting group, yields the propylbenzylamine143.

[0381] Substituted benzylamines can be prepared by the process outlinedin Scheme 41. The protected bromobenzylamine 140 is alkylated, such aswith propargyl alcohol in the presence of catalyst, such as PdCl₂(PPh₃),and CuI, in the presence of base, such as TEA, at a temperature aboveRT, preferably at a temperature above about 50° C., and more preferablyat a temperature at about 100° C., such as in a sealed tube, to form theprotected hydroxypropynylbenzylamine 144. The protectedhydroxypropynylbenzylamine is treated with N-methylmorpholine oxide inthe presence of a catalyst, such as tetrapropylammonium perruthenate, toform the aldehyde intermediate. Reductive amination, such as with theaddition of morpholine and NaBH(OAc)₃ provides the morpholinylderivative. Deprotection, such as with strong acid, such as TFA, forremoval of a Boc protecting group, yields the propylbenzylamine 145.

[0382] Substituted heterocycles may be prepared by the method found inScheme 42. Chloro-heterocycles 146 (where LG is OH) is coupled with anamine 147 at a suitable temperature, such as a temperature over about100° C. to give the 2-substituted amino-nicotinic acid 148. The2-substituted amino-nicotinic acid 148 is reacted with a substitutedamine in the presence of a coupling reagent, such as BOP-Cl and base,such as TEA to form the 2-substituted amino-nicotinamide 149.

[0383] Alternatively, 2-chloro-nicotinoyl chloride 146 (where LG is Cl)is coupled first with R²—NH₂, such as in the presence of base, e.g.,NaHCO₃, in a suitable solvent, such as IpOH or CH₂Cl₂, to form the amide150, then coupled with a benzylamine 147 to yield the 2-substitutedamino-nicotinamide 149. Where A is a pi-electron rich heterocycle, theaddition of KF, such as 40% KF on alumina in IpOH, at a temperature overabout 100° C., preferably about 160° C., can be used in the formation of149 from 150.

[0384] 2,3,4,4a,9,9a-Hexahydro-1H-3-aza-fluoren-6-ylamine may beprepared by the method found in Scheme 43. Nitrobenzylpyridines 151 arealkylated, such as with MeI, in the presence of TBAI and base to formthe pyridinium compound 152. The pyridinium compounds 152 arehalogenated, such as brominated with NBS, to form the brominatedpyridinium compounds 153 which are reduced such as with NaBH₄ to formthe tetrahydro-pyridines 154. Palladium catalyzed intramolecular Heckcoupling followed by hydrogenation forms the hexahydro-fluorenes 156.

[0385] The starting compounds defined in Schemes 1-43 may also bepresent with functional groups in protected form if necessary and/or inthe form of salts, provided a salt-forming group is present and thereaction in salt form is possible. If so desired, one compound ofFormula I-IV can be converted into another compound of Formula I-IV oran N-oxide thereof; a compound of Formula I-IV can be converted into asalt; a salt of a compound of Formula I-IV can be converted into thefree compound or another salt; and/or a mixture of isomeric compounds ofFormula I-IV can be separated into the individual isomers.

[0386] N-Oxides can be obtained in a known matter by reacting a compoundof Formula I-IV with hydrogen peroxide or a peracid, e.g.,3-chloroperoxy-benzoic acid, in an inert solvent, e.g., CH₂Cl₂, at atemperature between about −10-35° C., such as about 0° C.—RT.

[0387] If one or more other functional groups, for example carboxy,hydroxy, amino, or mercapto, are or need to be protected in a compoundof Formula I-IV or in the synthesis of a compound of Formula I-IV,because they should not take part in the reaction, these are such groupsas are usually used in the synthesis of peptide compounds, and also ofcephalosporins and penicillins, as well as nucleic acid derivatives andsugars.

[0388] The protecting groups may already be present in precursors andshould protect the functional groups concerned against unwantedsecondary reactions, such as acylations, etherifications,esterifications, oxidations, solvolysis, and similar reactions. It is acharacteristic of protecting groups that they lend themselves readily,i.e. without undesired secondary reactions, to removal, typically bysolvolysis, reduction, photolysis or also by enzyme activity, forexample under conditions analogous to physiological conditions, and thatthey are not present in the end-products. The specialist knows, or caneasily establish, which protecting groups are suitable with thereactions mentioned above and hereinafter.

[0389] The protection of such functional groups by such protectinggroups, the protecting groups themselves, and their removal reactionsare described for example in standard reference works, such as J. F. W.McOmie, “Protective Groups in Organic Chemistry”, Plenum Press, Londonand New York 1973, in T. W. Greene, “Protective Groups in OrganicSynthesis”, Wiley, New York 1981, in “The Peptides”; Volume 3 (editors:E. Gross and J. Meienhofer), Academic Press, London and New York 1981,in “Methoden der organischen Chemie” (Methods of organic chemistry),Houben Weyl, 4th edition, Volume 15/1, Georg Thieme Verlag, Stuttgart1974, in H.-D. Jakubke and H. Jescheit, “Aminosauren, Peptide, Proteine”(Amino acids, peptides, proteins), Verlag Chemie, Weinheim, DeerfieldBeach, and Basel 1982, and in Jochen Lehmann, “Chemie der Kohlenhydrate:Monosaccharide und Derivate” (Chemistry of carbohydrates:monosaccharides and derivatives), Georg Thieme Verlag, Stuttgart 1974.

[0390] In the additional process steps, carried out as desired,functional groups of the starting compounds which should not take partin the reaction may be present in unprotected form or may be protectedfor example by one or more of the protecting groups mentioned aboveunder “protecting groups”. The protecting groups are then wholly orpartly removed according to one of the methods described there.

[0391] Salts of a compound of Formula I-IV with a salt-forming group maybe prepared in a manner known per se. Acid addition salts of compoundsof Formula I-IV may thus be obtained by treatment with an acid or with asuitable anion exchange reagent. A salt with two acid molecules (forexample a dihalogenide of a compound of formula I) may also be convertedinto a salt with one acid molecule per compound (for example amonohalogenide); this may be done by heating to a melt, or for exampleby heating as a solid under a high vacuum at elevated temperature, forexample from about 130° C. to about 170° C., one molecule of the acidbeing expelled per molecule of a compound of Formula I-IV.

[0392] Salts can usually be converted to free compounds, e.g., bytreating with suitable basic agents, for example with alkali metalcarbonates, alkali metal hydrogen carbonates, or alkali metalhydroxides, typically potassium carbonate or sodium hydroxide.

[0393] A compound of formula I, wherein Z is oxygen, can be convertedinto the respective compound wherein Z is sulfur, for example, by usingan appropriate sulfur compound, e. g. using reaction with Lawesson'sreagent(2,4-bis-(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide)in a halogenated hydrocarbon, such as CH₂Cl₂, or an aprotic solvent,such as toluene or xylene, at temperatures from about 30° C. to reflux.

[0394] All process steps described here can be carried out under knownreaction conditions, preferably under those specifically mentioned, inthe absence of or usually in the presence of solvents or diluents,preferably such as are inert to the reagents used and able to dissolvethese, in the absence or presence of catalysts, condensing agents orneutralizing agents, for example ion exchangers, typically cationexchangers, for example in the H+ form, depending on the type ofreaction and/or reactants at reduced, normal, or elevated temperature,for example in the range from about −100° C. to about 190° C.,preferably from about −80° C. to about 150° C., for example at about −80to about 60° C., at RT, at about −20° C. to about 40° C. or at theboiling point of the solvent used, under atmospheric pressure or in aclosed vessel, where appropriate under pressure, and/or in an inertatmosphere, for example under argon or nitrogen.

[0395] Salts may be present in all starting compounds and transients, ifthese contain salt-forming groups. Salts may also be present during thereaction of such compounds, provided the reaction is not therebydisturbed.

[0396] In certain cases, typically in hydrogenation processes, it ispossible to achieve stereoselective reactions, allowing for exampleeasier recovery of individual isomers.

[0397] The solvents from which those can be selected which are suitablefor the reaction in question include for example water, esters,typically lower alkyl-lower alkanoates, e.g., ethyl acetate, ethers,typically aliphatic ethers, e.g., diethyl ether, or cyclic ethers, e.g.,THF, liquid aromatic hydrocarbons, typically benzene or toluene,alcohols, typically MeOH, EtOH or 1-propanol, IpOH, nitrites, typicallyCH₃CN, halogenated hydrocarbons, typically CH₂Cl₂, acid amides,typically DMF, bases, typically heterocyclic nitrogen bases, e.g.pyridine, carboxylic acids, typically lower alkanecarboxylic acids,e.g., AcOH, carboxylic acid anhydrides, typically lower alkane acidanhydrides, e.g., acetic anhydride, cyclic, linear, or branchedhydrocarbons, typically cyclohexane, hexane, or isopentane, or mixturesof these solvents, e.g., aqueous solutions, unless otherwise stated inthe description of the process. Such solvent mixtures may also be usedin processing, for example in chromatography.

[0398] The invention relates also to those forms of the process in whichone starts from a compound obtainable at any stage as a transient andcarries out the missing steps, or breaks off the process at any stage,or forms a starting material under the reaction conditions, or uses saidstarting material in the form of a reactive derivative or salt, orproduces a compound obtainable by means of the process according to theinvention and processes the said compound in situ. In the preferredembodiment, one starts from those starting materials which lead to thecompounds described above as preferred.

[0399] The compounds of Formula I-IV, including their salts, are alsoobtainable in the form of hydrates, or their crystals can include forexample the solvent used for crystallization (present as solvates).

[0400] New starting materials and/or intermediates, as well as processesfor the preparation thereof, are likewise the subject of this invention.In the preferred embodiment, such starting materials are used andreaction conditions so selected as to enable the preferred compounds tobe obtained.

[0401] Starting materials of the invention, are known, are commerciallyavailable, or can be synthesized in analogy to or according to methodsthat are known in the art.

[0402] For example, amine 1 can be prepared by reduction of thecorresponding nitro. The reduction preferably takes place in thepresence of a suitable reducing agent, such as tin(II) chloride orhydrogen in the presence of an appropriate catalyst, such as Raneynickel (then preferably the hydrogen is used under pressure, e.g.between 2 and 20 bar) or PtO₂, in an appropriate solvent, e.g. analcohol, such as MeOH. The reaction temperature is preferably betweenabout 0° C. and about 80° C., especially about 15° C. to about 30° C.

[0403] It would also be possible to reduce the nitro compound afterforming the amide compound under reaction conditions analogous to thosefor the reduction of nitro compounds described above. This wouldeliminate the need to protect the free amino group as described inScheme 1.

[0404] In the preparation of starting materials, existing functionalgroups which do not participate in the reaction should, if necessary, beprotected. Preferred protecting groups, their introduction and theirremoval are described above or in the examples.

[0405] All remaining starting materials are known, capable of beingprepared according to known processes, or commercially obtainable; inparticular, they can be prepared using processes as described in theexamples.

[0406] Compounds of the present invention can possess, in general, oneor more asymmetric carbon atoms and are thus capable of existing in theform of optical isomers as well as in the form of racemic or non-racemicmixtures thereof. The optical isomers can be obtained by resolution ofthe racemic mixtures according to conventional processes, e.g., byformation of diastereoisomeric salts, by treatment with an opticallyactive acid or base. Examples of appropriate acids are tartaric,diacetyltartaric, dibenzoyltartaric, ditoluoyltartaric, andcamphorsulfonic acid and then separation of the mixture ofdiastereoisomers by crystallization followed by liberation of theoptically active bases from these salts. A different process forseparation of optical isomers involves the use of a chiralchromatography column optimally chosen to maximize the separation of theenantiomers. Still another available method involves synthesis ofcovalent diastereoisomeric molecules by reacting compounds of theinvention with an optically pure acid in an activated form or anoptically pure isocyanate. The synthesized diastereoisomers can beseparated by conventional means such as chromatography, distillation,crystallization or sublimation, and then hydrolyzed to deliver theenantiomerically pure compound. The optically active compounds of theinvention can likewise be obtained by using optically active startingmaterials. These isomers may be in the form of a free acid, a free base,an ester or a salt.

[0407] The compounds of this invention may contain one or moreasymmetric centers and thus occur as racemates and racemic mixtures,scalemic mixtures, single enantiomers, individual diastereomers anddiastereomeric mixtures. All such isomeric forms of these compounds areexpressly included in the present invention.

[0408] The compounds of this invention may also be represented inmultiple tautomeric forms, for example, as illustrated below:

[0409] The invention expressly includes all tautomeric forms of thecompounds described herein.

[0410] The compounds may also occur in cis- or trans- or E- or Z-doublebond isomeric forms. All such isomeric forms of such compounds areexpressly included in the present invention. All crystal forms of thecompounds described herein are expressly included in the presentinvention.

[0411] Substituents on ring moieties (e.g., phenyl, thienyl, etc.) maybe attached to specific atoms, whereby they are intended to be fixed tothat atom, or they may be drawn unattached to a specific atom, wherebythey are intended to be attached at any available atom that is notalready substituted by an atom other than H (hydrogen).

[0412] The compounds of this invention may contain heterocyclic ringsystems attached to another ring system. Such heterocyclic ring systemsmay be attached through a carbon atom or a heteroatom in the ringsystem.

[0413] Alternatively, a compound of any of the formulas delineatedherein may be synthesized according to any of the processes delineatedherein. In the processes delineated herein, the steps may be performedin an alternate order and may be preceded, or followed, by additionalprotection/deprotection steps as necessary. The processes may furthercomprise use of appropriate reaction conditions, including inertsolvents, additional reagents, such as bases (e.g., LDA, DIEA, pyridine,K₂CO₃, and the like), catalysts, and salt forms of the above. Theintermediates may be isolated or carried on in situ, with or withoutpurification. Purification methods are known in the art and include, forexample, crystallization, chromatography (liquid and gas phase,simulated moving bed (“SMB”)), extraction, distillation, trituration,reverse phase HPLC and the like Reactions conditions such astemperature, duration, pressure, and atmosphere (inert gas, ambient) areknown in the art and may be adjusted as appropriate for the reaction.

[0414] As can be appreciated by the skilled artisan, the above syntheticschemes are not intended to comprise a comprehensive list of all meansby which the compounds described and claimed in this application may besynthesized. Further methods will be evident to those of ordinary skillin the art. Additionally, the various synthetic steps described abovemay be performed in an alternate sequence or order to give the desiredcompounds. Synthetic chemistry transformations and protecting groupmethodologies (protection and deprotection) useful in synthesizing theinhibitor compounds described herein are known in the art and include,for example, those such as described in R. Larock, Comprehensive OrganicTransformations, VCH Publishers (1989); T. W. Greene and P. G. M. Wuts,Protective Groups in Organic Synthesis, 3rd. Ed., John Wiley and Sons(1999); L. Fieser and M. Fieser, Fieser and Fieser's Reagents forOrganic Synthesis, John Wiley and Sons (1994); A. Katritzky and A.Pozharski, Handbook of Heterocyclic Chemistry, 2^(nd) Ed. (2001); M.Bodanszky, A. Bodanszky: The practice of Peptide SynthesisSpringer-Verlag, Berlin Heidelberg 1984; J. Seyden-Penne: Reductions bythe Alumino- and Borohydrides in Organic Synthesis, 2^(nd) Ed.,Wiley-VCH, 1997; and L. Paquette, ed., Encyclopedia of Reagents forOrganic Synthesis, John Wiley and Sons (1995).

[0415] The compounds of this invention may be modified by appendingappropriate functionalities to enhance selective biological properties.Such modifications are known in the art and include those which increasebiological penetration into a given biological compartment (e.g., blood,lymphatic system, central nervous system), increase oral availability,increase solubility to allow administration by injection, altermetabolism and alter rate of excretion.

[0416] The following examples contain detailed descriptions of themethods of preparation of compounds of Formulas I-IV. These detaileddescriptions fall within the scope, and serve to exemplify, the abovedescribed General Synthetic Procedures which form part of the invention.These detailed descriptions are presented for illustrative purposes onlyand are not intended as a restriction on the scope of the invention.

[0417] Unless otherwise noted, all materials were obtained fromcommercial suppliers and used without further purification. Anhydroussolvents such as DMF, THF, CH₂Cl₂ and toluene were obtained from theAldrich Chemical Company. All reactions involving air- ormoisture-sensitive compounds were performed under a nitrogen atmosphere.Flash chromatography was performed using Aldrich Chemical Company silicagel (200-400 mesh, 60A) or Biotage pre-packed column. Thin-layerchromatography (TLC) was performed with Analtech gel TLC plates (250 μ).Preparative TLC was performed with Analtech silica gel plates (1000-2000μ). Preparative HPLC was conducted on Beckman or Waters HPLC system with0.1% TFA/H₂O and 0.1% TFA/CH₃CN as mobile phase. The flow rate was at 20ml/min. and gradient method was used. ¹H NMR spectra were determinedwith super conducting FT NMR spectrometers operating at 400 MHz or aVarian 300 MHz instrument. Chemical shifts are expressed in ppmdownfield from internal standard tetramethylsilane. All compounds showedNMR spectra consistent with their assigned structures. Mass spectra (MS)were determined on a Perkin Elmer-SCIEX API 165 electrospray massspectrometer (positive and, or negative) or an HP 1100 MSD LC-MS witheletrospray ionization and quadrupole detection. All parts are by weightand temperatures are in Degrees centigrade unless otherwise indicated.

[0418] The following abbreviations are used: AcOH acetic acid Ac₂Oacetic anhydride AIBN 2,2′-azobisisobutyronitrile Ar argon AgSO₄ silversulfate AlCl₃ aluminum tricloride ATP adenosine triphosphate BH₃ boraneBoc tert-butyloxycarbonyl Boc₂O Boc anhydride BOP-Clbis(2-oxo-3-oxazolidinyl)phosphinic chloride BR₂ bromine BSA bovineserum albumin t-BuOH tert-butanol CAN ammonium cerium (IV) nitrateCH₃CN, AcCN acetonitrile CH₂Cl₂ dichloromethane CH₃I, MeI iodomethane,methyl iodide CCl₄ carbon tetrachloride CCl₃ chloroform CO₂ carbondioxide Cs₂CO₃ cesium carbonate DIEA diisopropylethylamine CuI copperiodide CuCN copper cyanide DCE 1,2-dichloroethane DEAD diethylazodicarboxylate DIEA diisopropylethylamine dppf1,1-diphenylphosphinoferrocene DMAP 4-(dimethylamino)pyridine DMACN,N-dimethylacetamide DMF dimethylformamide DMSO dimethylsulfoxide DTTdithiothreitol EDC, EDAC 1-(3-dimethylaminopropyl)-3- ethylcarbodiimidehydrochloride EGTA ethylene glycol-bis(β-aminoethyl ether)-N,N,N′,N′-tetraacetic acid EtOAc ethyl acetate EtOH ethanol Et₂O diethylether Fe iron g gram h hour HATU O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate H₂ hydrogen H₂O water HClhydrochloric acid H₂SO₄ sulfuric acid H₂NNH₂ hydrazine HC(OEt)₃triethylorthoformate HCHO, H₂CO formaldehyde HCO₂Na sodium formate HOAc,AcOH acetic acid HOAt 1-hydroxy-7-azabenzotriazole HOBthydroxybenzotriazole IpOH isopropanol KF potassium fluoride K₂CO₃potassium carbonate KHMDS potassium hexamethylsilazane KNO₃ potassiumnitrate KOAc potassium acetate KOR potassium hydroxide LAH, LiAlH₄lithium aluminum hydride LDA lithium diisopropylamide LiCl lithiumchloride LIHMDS lithium hexamethyldisilazide MeOH methanol MgCl₂magnesium chloride MgSO₄ magnesium sulfate mg milligram ml milliliterMnCl₂ manganese chloride NBS N-bromosuccinimide NMO 4 methylmorpholine,N-oxide NMP N-methylpyrrolidone Na₂SO₄ sodium sulfate Na₂S₂O₅ sodiummetabisulfite NaHSO₃ sodium bisulfite NaHCO₃ sodium bicarbonate Na₂CO₃sodium carbonate NaCl sodium chloride NaH sodium hydride NaI sodiumiodide NaOH sodium hydroxide NaOMe sodium methoxide NaOEt sodiumethoxide NaCNBH₃ sodium cyanoborohydride NaBH₄ sodium borohydride NaNO₂sodium nitrate NaBH(OAc)₃ sodium triacetoxyborohydride NH₄Cl ammoniumchloride N₂ nitrogen Pd/C palladium on carbon PdCl₂(PPh₃)₂ palladiumchloride bis(triphenylphosphine) PdCl₂(dppf)1,1-bis(diphenylphosphino)ferrocene palladium chloride Pd(PPh₃)₄palladium tetrakis triphenylphosphine Pd(OH)₂ palladium hydroxidePd(OAc)₂ palladium acetate PMB para methoxybenzyl POCl₃ phosphorusoxychloride PPh₃ triphenylphosphine PtO₂ platinum oxide RT roomtemperature SiO₂ silica SOCl₂ thionyl chloride TBAI tetrabutylammoniumiodide TBTU O-(1H-benzotriazol-1-yl)-N,N,N′,N′- tetramethyluroniumtetrafluoroborate TEA triethylamine Tf₂NPhN-phenyltrifluoromethanesulfonimide TFA trifluoroacetic acid THFtetrahydrofuran TPAP tetrapropylammoniumperruthenate Tris-HClTris(hydroxymethyl)aminomethane hydrochloride salt Zn zinc

Preparation I-3-nitro-5-trifluoromethyl-phenol

[0419] 1-Methoxy-3-nitro-5-trifluoromethyl-benzene (10 g, Aldrich) andpyridine-HCl (41.8 g, Aldrich) were mixed together and heated neat at210° C. in an open flask. After 2.5 h the mixture was cooled to RT andpartitioned between 1N HCl and EtOAc. The EtOAc fraction was washed with1N HCl (4×), brine (1×), dried with Na₂SO₄, filtered and concentrated invacuo to form 3-nitro-5-trifluoromethyl-phenol as an off-white solid.

Preparation II-1-Boc-4-(3-nitro-5-trifluoromethyl-phenoxy)-piperidine

[0420] 3-Nitro-5-trifluoromethyl-phenol (8.8 g) was dissolved in THF (76ml). 1-Boc-4-hydroxy-piperidine (8.81 g, Aldrich) and Ph₃P (11.15 g)were added and the solution was cooled to −20° C. A solution of DEAD(6.8 ml, Aldrich) in THF (36 ml) was added dropwise, maintaining thetemperature between −20 and −10° C. The reaction was warmed to RT andstirred overnight. The reaction was concentrated in vacuo and trituratedwith hexane. The yellow solid was removed by filtration and washed withEt₂O (25 ml), and hexane. The white filtrate was washed with 1N NaOH(2×), brine (1×) and the hexane layer was dried over Na₂SO₄, filteredand concentrated in vacuo. The crude material was purified with flashchromatography (SiO₂, 5-10% EtOAc/hexane) to obtain1-Boc-4-(3-nitro-5-trifluoromethyl-phenoxy)-piperidine.

[0421] The following compounds were prepared similarly to the procedureoutlined above:

[0422] a)(S)-1-Boc-[2-(5-nitro-2-trifluoromethylphenoxymethyl]-pyrrolidine

[0423] b)(R)-1-Boc-[2-(5-nitro-2-trifluoromethylphenoxymethyl]-pyrrolidine.

[0424] c) (R)1-Boc-2-(3-Nitro-5-trifluoromethyl-phenoxymethyl)-pyrrolidine

[0425] d) 4-(2-tert-Butyl-5-nitro-phenoxymethyl)-1-methyl-piperidine.

[0426] e) (S)1-Boc-2-(3-Nitro-5-trifluoromethyl-phenoxymethyl)-pyrrolidine

[0427] f) 1-Boc-3-(5-nitro-2-pentafluoroethyl-phenoxymethyl)-azetidine.

[0428] g) N-Boc-[2-(5-nitro-2-pentafluoroethyl-phenoxy)-ethyl]amine.

[0429] h) (R) 3-(2-tert-Butyl-5-nitro-phenoxymethyl)-1-Boc-pyrrolidine.

[0430] i) 3-(2-tert-Butyl-5-nitro-phenoxymethyl)-1-Boc-azetidine.

[0431] j) (S)-1-Boc-[2-(5-nitro-2-tert-butylphenoxymethyl]-pyrrolidine

[0432] k) (S) 3-(2-tert-Butyl-5-nitro-phenoxymethyl)-1-Boc-pyrrolidine.

[0433] l) (R)-1-Boc-[2-(5-nitro-2-tert-butylphenoxymethyl]-pyrrolidine

Preparation III-1-Boc-4-(3-amino-5-trifluoromethyl-phenoxy)-piperidine

[0434] 1-Boc-4-(3-nitro-5-trifluoromethyl-phenoxy)-piperidine (470 mg)was dissolved in MeOH (12 ml) and Pd/C (10 mg) was added. After spargingbriefly with H₂, the mixture was stirred under H₂ for 6 H. The catalystwas removed by filtration and the MeOH solution was concentrated invacuo to yield 1-Boc-4-(3-amino-5-trifluoromethyl-phenoxy)-piperidine asan off-white foam.

[0435] The following compounds were prepared similarly to the procedureoutlined above:

[0436] a) 1-Boc-2-(3-Amino-5-trifluoromethyl-phenoxymethyl)-pyrrolidine.

[0437] b)2-(3-Amino-5-trifluoromethyl-phenoxymethyl)-1-methyl-pyrrolidine.

[0438] c) [2-(1-Methylpiperidin-4-yloxy)-pyridin-4-yl]methylamine. ESI(M+H)=222.

[0439] d) [2-(2-Morpholin-4-yl-ethoxy)-pyridin-4-yl]methylamine.

[0440] e) [2-(2-Morpholin-4-yl-propoxy)-pyridin-4-yl]methylamine.

[0441] f) [2-(1-Methyl-pyrrolidin-2-ylmethoxy)-pyridin-4-yl]methylamine.ESI MS: (M+H)=222.

[0442] g) (4-Aminomethyl-pyridin-2-yl)-(3-morpholin-4-yl-propyl)-amine.ESI MS: (M+H)=251.

[0443] h) 4-tert-Butyl-3-(1-methyl-piperidin-4-ylmethoxy)-phenylamine.

[0444] i) 4-tert-Butyl-3-(2-piperidin-1-yl-ethoxy)-phenylamine.

[0445] j)3-(1-Methyl-piperidin-4-ylmethoxy)-4-pentafluoroethyl-phenylamine.

[0446] k)3-(1-Isopropyl-piperidin-4-ylmethoxy)-4-pentafluoroethyl-phenylamine.

[0447] 1) (S) 3-Oxiranylmethoxy-4-pentafluoroethyl-phenylamine.

[0448] m) 3-(2-Pyrrolidin-1-yl-ethoxy)-4-trifluoromethyl-phenylamine.

[0449] n) 3-(2-Piperidin-1-yl-ethoxy)-4-trifluoromethyl-phenylamine.

[0450] o) (S)3-(1-Boc-pyrrolidin-2-ylmethoxy)-4-pentafluoroethyl-phenylamine.

[0451] p) (R)3-(1-Boc-pyrrolidin-2-ylmethoxy)-4-pentafluoroethyl-phenylamine.

[0452] q) (R)3-(1-Methyl-pyrrolidin-2-ylmethoxy)-5-trifluoromethyl-phenylamine.

[0453] r) (S)3-(1-Methyl-pyrrolidin-2-ylmethoxy)-5-trifluoromethyl-phenylamine

[0454] s) (R) 3-Oxiranylmethoxy-4-pentafluoroethyl-phenylamine.

[0455] t) (R)2-(5-Amino-2-pentafluoroethyl-phenoxy)-1-pyrrolidin-1-yl-ethanol.

[0456] u) 3-(1-Boc-azetidin-3-ylmethoxy)-4-pentafluoroethyl-phenylamine.

[0457] v) 3-(2-(Boc-amino)ethoxy)-4-pentafluoroethyl-phenylamine.

[0458] w) 6-Amino-2,2-dimethyl-4H-benzo[1,4]oxazin-3-one. M+H 193.2.Calc'd 192.1.

[0459] x) 2,2,4-Trimethyl-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylamine.

[0460] y)1-(6-Amino-2,2-dimethyl-2,3-dihydro-benzo[1,4]oxazin-4-yl)-ethanone. M+H221.4. Calc'd 220.3.

[0461] z) [2-(1-Benzhydryl-azetidin-3-yloxy)-pyridin-4-yl]-methylamine.

[0462] aa)[2-(1-Methyl-piperidin-4-ylmethoxy)-pyridin-4-yl]-methylamine. M+H236.3. Calc'd 235.2.

[0463] ab) 3-(4-Boc-piperazin-1-ylmethyl)-5-trifluoromethyl-phenylamine.M+H 360.3.

[0464] ac) 2-Boc-4,4-dimethyl-1,2,3,4-tetrahydro-isoquinolin-7-ylamine.

[0465] ad) 3-Morpholin-4-ylmethyl-4-pentafluoroethyl-phenylamine.

[0466] ae)3-(4-Methyl-piperazin-1-ylmethyl)-4-pentafluoroethyl-phenylamine. M+H410.3. Calc'd 409.4.

[0467] af)7-Amino-2-(4-methoxy-benzyl)-4,4-dimethyl-3,4-dihydro-2H-isoquinolin-1-one.M+H 311.1.

[0468] ag) 7-Amino-4,4-dimethyl-3,4-dihydro-2H-isoquinolin-1-one.

[0469] ah)(3-Amino-5-trifluoromethyl-phenyl)-(4-Boc-piperazin-1-yl)-methanone. M+H374.3; Calc'd 373.

[0470] ai) 3-(4-Boc-Piperazin-1-ylmethyl)-5-trifluoromethyl-phenylamine.

[0471] aj)1-(7-Amino-4,4-dimethyl-3,4-dihydro-1-isoquinolin-2-yl)-ethanone. M+H219.2.

[0472] ak){2-[2-(1-Methylpiperidin-4-yl)ethoxy]-pyridin-4-yl}-methylamine.

[0473] al) {2-[2-(1-Pyrrolidinyl)ethoxy]-pyridin-4-yl}-methylamine.

[0474] am){2-[2-(1-Methylpyrrolin-2-yl)ethoxy]-pyridin-4-yl}-methylamine.

[0475] an) (2-Chloro-pyrimidin-4-yl)-methylamine.

[0476] ao) 3-(1-Boc-azetidin-3-ylmethoxy)-5-trifluoromethyl-phenylamine.

[0477] ap) 4-tert-Butyl-3-(1-Boc-pyrrolidin-3-ylmethoxy)-phenylamine.M+H 385.

[0478] aq) 4-tert-Butyl-3-(1-Boc-azetidin-3-ylmethoxy)-phenylamine. M+Na357.

[0479] ar) (S)4-tert-Butyl-3-(1-Boc-pyrrolidin-2-ylmethoxy)-phenylamine. M+Na 371.

[0480] as) 3-tert-Butyl-4-(4-Boc-piperazin-1-yl)-phenylamine

[0481] at) 3-(1-Methyl-piperidin-4-yl)-5-trifluoromethyl-phenylamine.

[0482] au) 3,3-Dimethyl-2,3-dihydro-benzofuran-6-ylamine.

[0483] av)3,9,9-Trimethyl-2,3,4,4a,9,9a-hexahydro-1H-3-aza-fluoren-6-ylamine.

[0484] aw) 4-[1-Methyl-1-(1-methyl-piperidin-4-yl)-ethyl]-phenylaminewas prepared using EtOH as the solvent.

[0485] ax) 4-tert-Butyl-3-(4-pyrrolidin-1-yl-but-1-enyl)-phenylamine.

[0486] ay) (R)3-(1-Boc-pyrrolidin-2-ylmethoxy)-5-trifluoromethyl-phenylamine.

[0487] az) (S)3-(1-Boc-pyrrolidin-2-ylmethoxy)-5-trifluoromethyl-phenylamine.

PreparationIV-1-Boc-4-{3-[(2-fluoro-pyridine-3-carbonyl)-amino]-5-trifluoromethyl-phenoxy}-piperidine

[0488]1-Boc-4-(3-amino-5-trifluoromethyl-phenoxy)-piperidine (4.37 g)was dissolved in CH₂Cl₂ (100 ml) and NaHCO₃ (2.4 g, Baker) was added.2-Fluoropyridine-3-carbonyl chloride (2.12 g) was added an the reactionwas stirred at RT for 2.5 h. The reaction was filtered and concentratedin vacuo to yield a yellow foam. (30%) EtOAc/Hexane was added andl-Boc-4-{3-[(2-fluoro-pyridine-3-carbonyl)-amino]-5-trifluoromethyl-phenoxy}-piperidineprecipitated as an off white solid.

[0489] The following compounds were prepared similarly to the procedureoutlined above:

[0490] a)2-Fluoro-N-[3-(3-piperidin-1-yl-propyl)-5-trifluoromethyl-phenyl]-nicotinamide.

[0491] b)N-[4-tert-Butyl-3-(2-piperidin-1-yl-ethoxy)-phenyl]-2-fluoro-nicotinamide.

[0492] c)N-[3,3-Dimethyl-1-(1-methyl-piperidin-4-ylmethyl)-2,3-dihydro-1-indol-6-yl]-2-fluoro-nicotinamide.

[0493] d)N-[1-(2-Dimethylamino-acetyl)-3,3-dimethyl-2,3-dihydro-1-indol-6-yl]-2-fluoro-nicotinamide

[0494] e)N-[3,3-Dimethyl-1-(2-(Boc-amino)acetyl)-2,3-dihydro-1H-indol-6-yl]-2-fluoro-nicotinamide.

[0495] f)N-(4-Acetyl-2,2-dimethyl-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl)-2-fluoro-nicotinamide.M+H 344.5. Calc'd 343.4.

[0496] g)2-Fluoro-N-(2,2,4-trimethyl-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl)-nicotinamide.M+H 316.2. Calc'd 315.1.

[0497] h)N-(2,2-Dimethyl-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl)-2-fluoro-nicotinamide.M+H 316.1. Calc'd 315.10.

[0498] i)2-Fluoro-N-[3-(4-methyl-piperazin-1-ylmethyl)-5-trifluoromethyl-phenyl]-nicotinamide. M+H 481. Calc'd 480.

[0499] j)2-Fluoro-N-(2-Boc-4,4-dimethyl-1,2,3,4-tetrahydro-isoquinolin-7-yl)-nicotinamide.M+H 400.

[0500] k)2-Fluoro-N-[3-(4-methyl-piperazin-1-ylmethyl)-4-pentafluoroethyl-phenyl]-nicotinamide. M+H 447.0. Calc'd 446.

[0501] l)2-Fluoro-N-(3-morpholin-4-ylmethyl-4-pentafluoroethyl-phenyl)-nicotinamide.

[0502] m) 2-Fluoro-N-[4-iodophenyl]-nicotinamide.

[0503] n)2-Fluoro-N-(4,4-dimethyl-1-oxo-1,2,3,4-tetrahydro-isoquinolin-7-yl)-nicotinamide.M+H 314.0, Calc'd 311.

[0504] o)2-Fluoro-N-[3-(4-Boc-piperazine-1-carbonyl)-5-trifluoromethyl-phenyl]-nicotinamide. M+H 495.

[0505] p)2-Fluoro-N-[3-(4-Boc-piperazin-1-ylmethyl)-5-trifluoromethyl-phenyl]-nicotinamide. M+H 483.3; Calc'd 482.

[0506] q)N-(2-Acetyl-4,4-dimethyl-1,2,3,4-tetrahydro-isoquinolin-7-yl)-2-fluoro-nicotinamide.M+H 430.0.

[0507] r)N-[3,3-Dimethyl-1-(1-methyl-piperidin-4-yl)-2,3-dihydro-1H-indol-6-yl]-2-fluoro-nicotinamide.M+H 383.2; Calc'd 382.5.

[0508] s) N-(4-tert-Butylphenyl)-2-fluoronicotinamide.

[0509] t) N-(4-Trifluoromethylphenyl)-2-fluoronicotinamide.

[0510] u)2-Fluoro-N-[3-(1-Boc-azetidin-3-ylmethoxy)-5-trifluoromethyl-phenyl]-nicotinamide. M-H 468.2; Calc'd 469.16.

[0511] v)2-Fluoro-N-[3-(1-Boc-azetidin-3-ylmethoxy)-4-tert-butyl-phenyl]-nicotinamide.

[0512] w) (S)N-[4-tert-Butyl-3-(1-Boc-pyrrolidin-2-ylmethoxy)-phenyl]-2-fluoro-nicotinamide.M+Na 494.

[0513] x)N-[3-(1-Methyl-piperidin-4-yl)-5-trifluoromethyl-phenyl]-2-fluoro-nicotinamidewas prepared with K₂CO₃. instead of NaHCO₃.

[0514] y) N-(3-Bromo-5-trifluoromethyl-phenyl)-2-fluoro-nicotinamide.

[0515] z)2-Fluoro-N-(3,9,9-trimethyl-2,3,4,4a,9,9a-hexahydro-1-3-aza-fluoren-6-yl)-nicotinamide.

[0516] aa) 2-Fluoro-N-{4-[1-methyl-1-(1-methyl-piperidin-4-yl)-ethyl]-phenyl}-nicotinamide

[0517] ab)N-[3,3-Dimethyl-1-(1-Boc-piperidin-4-ylmethyl)-2,3-dihydro-1-indol-6-yl]-2-fluoro-nicotinamide.

PreparationV-1-Boc-4-{3-[(2-chloro-pyridine-3-carbonyl)-amino]-5-trifluoromethyl-phenoxy}-piperidine

[0518]1-Boc-4-{3-[(2-chloro-pyridine-3-carbonyl)-amino]-5-trifluoromethyl-phenoxy}-piperidine was prepared from1-Boc-4-(3-amino-5-trifluoromethyl-phenoxy)-piperidine and2-chloropyridine-3-carbonyl chloride by a procedure similar to thatdescribed in the preparation of1-Boc-4-{3-[(2-fluoro-pyridine-3-carbonyl)-amino]-5-trifluoromethyl-phenoxy}-piperidine.

[0519] The following compounds were prepared similarly to the procedureoutlined above:

[0520] a) N-(4-tert-Butyl-3-nitro-phenyl)-2-chloro-nicotinamide.

[0521] b)2-Chloro-N-[3-(3-piperidin-1-yl-propyl)-5-trifluoromethyl-phenyl]-nicotinamide.

[0522] c)2-Chloro-N-[3-(3-morpholin-4-yl-propyl)-5-trifluoromethyl-phenyl]-nicotinamide.

[0523] d)2-Chloro-N-[3-(1-methylpiperidin-4-yl)-5-trifluoromethyl-phenyl]-nicotinamide.

[0524] e)2-Chloro-N-[3-(1-methyl-piperidin-4-ylmethoxy)-4-pentafluoroethyl-phenyl]-nicotinamide.

[0525] f)2-Chloro-N-[3-(1-isopropyl-piperidin-4-ylmethoxy)-4-pentafluoroethyl-phenyl]-nicotinamide.

[0526] g) (S)2-Chloro-N-[4-(oxiranylmethoxy)-3-pentafluoroethyl-phenyl]-nicotinamide.

[0527] h)2-Chloro-N-[3-(2-pyrrolidin-1-yl-ethoxy)-4-trifluoromethyl-phenyl]-nicotinamide.

[0528] i)2-Chloro-N-[3-(2-piperidin-1-yl-ethoxy)-4-pentafluoroethyl-phenyl]-nicotinamide.

[0529] j) (R)2-Chloro-N-[3-(1-Boc-pyrrolidin-2-ylmethoxy)-4-pentafluoroethyl-phenyl]-nicotinamide.

[0530] k) (S)2-Chloro-N-[3-(1-Boc-pyrrolidin-2-ylmethoxy)-4-pentafluoroethyl-phenyl]-nicotinamide.

[0531] l) (R)2-Chloro-N-[3-(1-methyl-pyrrolidin-2-ylmethoxy)-5-trifluoromethyl-phenyl]-nicotinamide.

[0532] m) (S)2-Chloro-N-[3-(1-methyl-pyrrolidin-2-ylmethoxy)-5-trifluoromethyl-phenyl]-nicotinamide.

[0533] n) (R)2-Chloro-N-[4-(oxiranylmethoxy)-3-pentafluoroethyl-phenyl]-nicotinamide.

[0534] o) (R) Acetic acid2-{5-[(2-chloro-pyridine-3-carbonyl)-amino]-2-pentafluoroethyl-phenoxy}-1-pyrrolidin-1-yl-ethylester.

[0535] p)2-Chloro-N-[3-(4-methyl-piperazin-1-ylmethyl)-5-trifluoromethyl-phenyl]-nicotinamide.

[0536] q)2-Chloro-N-[2-(4-methoxy-benzyl)-4,4-dimethyl-1-oxo-1,2,3,4-tetrahydro-isoquinolin-7-yl]-nicotinamide.M+H 450.2. Calc'd 449.

[0537] r)2-Chloro-N-(4,4-dimethyl-1-oxo-1,2,3,4-tetrahydro-isoquinolin-7-yl)-nicotinamide.M+H 330.1, Calc'd 329.

[0538] s)2-Chloro-N-[3-(4-Boc-piperazin-1-ylmethyl)-5-trifluoromethyl-phenyl]-nicotinamide.

[0539] t)2-{3-[(2-Chloro-pyridine-3-carbonyl)-amino]-phenyl}-2-methyl-propionicacid methyl ester. M+H 405

[0540] u)N-{4-tert-Butyl-3-[2-(1-Boc-piperidin-4-yl)-ethyl]-phenyl}-2-chloro-nicotinamide.M+Na 524. Calc'd 501.1.

[0541] v)N-[3,3-Dimethyl-1,1-dioxo-2,3-dihydro-1H-benzo[d]isothiazol-6-yl]-2-chloro-nicotinamide.

[0542] w)N-[1,1,4,4-Tetramethyl-1,2,3,4-tetrahydro-naphth-6-yl]-2-chloro-nicotinamide.

[0543] x)2-Chloro-N-[3,3-dimethyl-2,3-dihydro-benzofuran-6-yl]-2-chloro-nicotinamide.

[0544] y)2-Chloro-N-[3-(1-Boc-piperidin-4-yloxy)-5-trifluoromethyl-phenyl]-nicotinamide.

[0545] z)2-Chloro-N-[3-(1-methyl-piperidin-4-ylmethyl)-5-trifluoromethyl-phenyl]-nicotinamide.

[0546] aa)2-Chloro-N-[3-(3-piperidin-1-yl-propyl)-5-trifluoromethyl-phenyl]-nicotinamide.

[0547] ab)N-[4-tert-Butyl-3-(4-pyrrolidin-1-yl-but-1-enyl)-phenyl]-2-chloro-nicotinamide.

[0548] ac) (R)2-Chloro-N-[3-(1-Boc-pyrrolidin-2-ylmethoxy)-5-trifluoromethyl-phenyl]-nicotinamide.

[0549] ad) (S)2-Chloro-N-[3-(1-Boc-pyrrolidin-2-ylmethoxy)-5-trifluoromethyl-phenyl]-nicotinamide.

PreparationVI-1-Boc-2-{3-[(2-fluoro-pyridine-3-carbonyl)-amino]-5-trifluoromethyl-phenoxymethyl}-pyrrolidine

[0550]1-Boc-2-{3-[(2-Fluoro-pyridine-3-carbonyl)-amino]-5-trifluoromethyl-phenoxymethyl}-pyrrolidinewas prepared from1-Boc-2-(3-amino-5-trifluoromethyl-phenoxymethyl)-pyrrolidine by aprocedure similar to that described in the preparation of1-Boc-4-{3-[(2-fluoro-pyridine-3-carbonyl)-amino]-5-trifluoromethyl-phenoxy}-piperidine.

Preparation VII-2-(3-nitro-5-trifluoromethyl-phenoxymethyl)-pyrrolidine

[0551] 1-Boc-2-(3-nitro-5-trifluoromethyl-phenoxymethyl)-pyrrolidine(2.35 g) was dissolved in CH₂Cl₂ (60 ml) and TFA (20 ml) was added.After stirring for 1 h at RT, the mixture was concentrated in vacuo toyield 2-(3-nitro-5-trifluoromethyl-phenoxymethyl)-pyrrolidine as an oilthat solidified upon standing. The material was used as is withoutfurther purification.

[0552] The following compounds were prepared similarly to the procedureoutlined above:

[0553] a)(4-Aminomethyl-pyrimidin-2-yl)-(3-morpholin-4-yl-propyl)-amine.

[0554] b)(4-Aminomethyl-pyrimidin-2-yl)-[2-(1-methyl-pyrrolidin-2-yl)-ethyl]-amine.

PreparationVIII-1-methyl-2-(3-nitro-5-trifluoromethyl-phenoxymethyl)-pyrrolidine

[0555] 2-(3-Nitro-5-trifluoromethyl-phenoxymethyl)-pyrrolidine (6mmol)was dissolved in CH₃CN (20 ml) and formaldehyde (2.4 ml, 37%aqueous) was added. NaBH₃CN (607 mg) was added, an exotherm wasobserved. The pH is monitored every 15 min and adjusted to ˜7 with AcOH.After 45 min, the mixture was concentrated in vacuo and the residue isdissolved in EtOAc, washed with 6N NaOH, 1N NaOH, and 2N HCl (3×). Theacid washings were combined, adjusted to ˜pH 10 with solid Na₂CO₃ andextracted with EtOAc (2×). The EtOAc fractions were combined, dried withNa₂SO₄, and purified with flash chromatography (SiO₂, 95:5:0.5CH₂Cl₂:MeOH:NH₄OH) to afford1-methyl-2-(3-nitro-5-trifluoromethyl-phenoxymethyl)-pyrrolidine.

[0556] The following compounds were prepared similarly to the procedureoutlined above:

[0557] a) 2-(1-Methylpiperidin-4-yl)-ethanol.

[0558] b)2-{3-[(2-Fluoro-pyridine-3-carbonyl)-amino]-5-trifluoromethyl-phenoxymethyl}-1-methylpyrrolidine.

Preparation IX-4-tert-butyl-3-nitro-phenylamine

[0559] A mixture of 1,3-dinitro-4-tert-butylbenzene (10.0 g) in H₂O (56ml) was heated to reflux. A mixture of Na₂S (21.42 g) and sulfur (2.85g) in H₂O (34 ml) was added over 1 h via an addition funnel. Thereaction maintained at reflux for 1.5 h then cooled to RT and extractedwith EtOAc. The organic extracts were combined and washed with H₂O,brine, dried over MgSO₄ and concentrated in vacuo to afford4-tert-butyl-3-nitro-phenylamine which was used as is without furtherpurification.

Preparation X-N-(3-bromo-5-trifluoromethyl-phenyl)-acetamide

[0560] 3-Bromo-5-(trifluoromethyl)phenylamine (5 g, Alfa-Aesar) wasdissolved in AcOH (140 ml) and Ac₂0 (5.9 ml, Aldrich) was added. Thereaction was stirred at RT overnight. The mixture was added slowly toH₂O (˜700 ml) forming a white precipitate. The solid was isolated byfiltration, washed with H₂O and dried under vacuum to yieldN-(3-bromo-5-trifluoromethyl-phenyl)-acetamide.

PreparationXI-N-[3-(3-piperidin-1-yl-propyl)-5-trifluoromethyl-phenyl]-acetamide

[0561] Allylpiperidine (1.96 g, Lancaster) was degassed under vacuum,dissolved in 0.5 M 9-BBN in THF (31.2 ml, Aldrich), and heated to refluxfor 1 h, then cooled to RT. PD(dppf)Cl₂/CH₂Cl₂ was added to a degassedmixture of N-(3-bromo-5-trifluoromethyl-phenyl)-acetamide, K₂CO₃ (9.8 g)DMF (32.1 ml and H₂O (3 ml). The allyl piperidine solution was addedheated to 60° C. for 3 h. After cooling to RT and reheating at 60° C.for 6 h, the mixture was cooled to RT and poured into H₂0. The mixturewas extracted with EtOAc (2×), and the EtOAc portion was washed with 2 NHCl (2×) and brine. The aqueous phases were combined and the pH wasadjusted to ˜11 with NaOH (15%) forming a cloudy suspension. The cloudysuspension was extracted with EtOAc (2×) and the EtOAc portion was driedwith Na₂SO₄, filtered and concentrated in vacuo. The crude material waspurified by flash chromatography (SiO₂, 95:5:0.5 CH₂Cl₂:MeOH:NH₄0H) toafford N-[3-(3-piperidin-1-yl-propyl)-5-trifluoromethyl-phenyl]-acetamide as a brown oil that solidified under vacuum.

[0562] The following compounds were prepared similarly to the procedureoutlined above:

[0563] a) N-(3-Morpholin-4-ylpropyl-5-trifluoromethyl-phenyl)-acetamidefrom 4-allyl-morpholine.

[0564] b)N-(3-(1-methylpiperdin-4-ylmethyl-5-trifluoromethyl-phenyl)-acetamidefrom 1-Methyl-4-methylene-piperidine.

PreparationXII-3-(3-piperidin-1-yl-propyl)-5-trifluoromethyl-phenylamine

[0565]N-[3-(3-Piperidin-1-yl-propyl)-5-trifluoromethyl-phenyl]-acetamide (1.33g) was dissolved in EtOH (40 ml) and 12 N HCl (40 ml) was added. Afterstirring overnight at 70° C. and RT, the mixture was concentrated invacuo, affording3-(3-piperidin-1-yl-propyl)-5-trifluoromethyl-phenylamine as a brownoil.

[0566] The following compounds were prepared similarly to the procedureoutlined above:

[0567] a) 3,3-Dimethyl-6-nitro-2,3-dihydro-1H-indole. M+H 193.1; Calc'd192.2.

[0568] b)3-(1-Methyl-piperidin-4-ylmethyl)-5-trifluoromethyl-phenylamine.

[0569] c) 3-Morpholin-4-ylmethyl-5-trifluoromethyl-phenylamine.

PreparationXIII-3,3-Dimethyl-6-nitro-1-piperidin-4-ylmethyl-2,3-dihydro-1-indole

[0570]3,3-Dimethyl-1-(1-Boc-piperidin-4-ylmethyl)-6-nitro-2,3-dihydro-1-indolewas dissolved in HCl/EtOAc and stirred for 2 h. The mixture wasconcentrated in vacuo and partitioned between 1,2-dichloroethane and 1NNaOH. The organic layer was removed, washed with brine, dried (Na₂SO₄)and filtered. The material was used without further purification.

PreparationXIV-N-[3-(3-morpholin-4-yl-propyl)-5-trifluoromethyl-phenyl]-acetamide

[0571]N-[3-(3-Morpholin-4-yl-propyl)-5-trifluoromethyl-phenyl]-acetamide wasprepared from allyl morpholine andN-(3-bromo-5-trifluoromethyl-phenyl)-acetamide similar to that describedin the preparation of N[3-(3-piperidin-1-yl-propyl)-5-trifluoromethyl-phenyl]-acetamide.

Preparation XV-3-(3-morpholin-4-yl-propyl)-5-trifluoromethyl-phenylamine

[0572] 3-(3-Morpholin-4-yl-propyl)-5-trifluoromethyl-phenylamine wasprepared fromN-[3-(3-morpholin-4-yl-propyl)-5-trifluoromethyl-phenyl]-acetamidesimilar to that described in the preparation of3-(3-piperidin-1-yl-propyl)-5-trifluoromethyl-phenylamine.

Preparation XVI-1-methyl-4-methylene-piperidine

[0573] Ph₃PCH₃I (50 g, Aldrich) was suspended in Et₂O (20 ml) andbutyllithium (77.3 ml, 1.6 M in hexanes, Aldrich) was added dropwise.The reaction was stirred for 2 h at RT then 1-methylpiperidone (12.3 ml,Aldrich) was added slowly. The mixture was stirred at RT overnight. Thesolid was removed by filtration, the volume was reduced to ˜400 ml andadditional solid was removed by filtration. The Et₂O was washed with H20(2×) and 2N HCl (4×). The pH of the acid washings was adjusted to ˜11with 6 N NaOH, then they were extracted with CH₂Cl₂ (4×). The CH2Cl₂washings were dried over Na₂SO₄ and concentrated cold in vacuo toprovide 1-methyl-4-methylene-piperidine which was used as is.

PreparationXVII-N-[3-(1-methylpiperidin-4-yl)-5-trifluoromethyl-phenyl]-acetamide

[0574] N-[3-(1-Methylpiperidin-4-yl)-5-trifluoromethyl-phenyl]-acetamidewas prepared from 1-methyl-4-methylene-piperidine andN-(3-bromo-5-trifluoromethyl-phenyl)-acetamide similar to that describedin the preparation ofN-[3-(3-piperidin-1-yl-propyl)-5-trifluoromethyl-phenyl]-acetamide.

PreparationXVIII-3-(1-methylpiperidin-4-yl)-5-trifluoromethyl-phenylamine

[0575] 3-(1-Methylpiperidin-4-yl)-5-trifluoromethyl-phenylamine wasprepared fromN-[3-(1-methylpiperidin-4-yl)-5-trifluoromethyl-phenyl]-acetamidesimilar to the procedure described in the preparation of3-(3-piperidin-1-yl-propyl)-5-trifluoromethyl-phenylamine.

Preparation XIX-2-(1-methylpiperidin-4-yloxy)-4-pyridylcarbonitrile

[0576] 4-Hydroxy-1-methylpiperidine (25.4 g) was dissolved in THF (50ml) in a 100 mL r.b. flask. NaH/mineral oil mixture (9.58 g) was slowlyadded to the flask and stirred for 20 min. 2-Chloro-4-cyanopyridine wasadded to the mixture and stirred at RT until completion. Diluted mixturewith EtOAc and added H₂O to quench mixture, then transferred contents toa sep. funnel. The organic phase was collected while the aqueous phasewas washed two times with EtOAc. The combined organics were dried overNa₂SO₄, filtered, then concentrated in vacuo. Then redissolved mixturein CH₂Cl₂, 10% HCl (300 ml) was added and the mixture was transferred tosep. funnel. The org. was extracted, while EtOAc along with 300 mL 5NNaOH was added to the sep. funnel. The organic phases were collected,dried over Na₂SO₄, filtered and concentrated in vacuo affording2-(1-methylpiperidin-4-yloxy)-4-pyridylcarbonitrile as a brown solid.ESI (M+H)=218.

[0577] The following compounds were prepared similarly to the procedureoutlined above:

[0578] a) 2-(1-methylpiperidin-4-ylmethoxy)-4-pyridylcarbonitrile.

[0579] M+H 232.1. Calc'd 231.1.

[0580] b) 2-(1-Benzhydryl-azetidin-3-yloxy)-4-pyridylcarbonitrile.

[0581] M+H 342.2. Calc'd 341.2.

[0582] c) 2-(1-methylpiperidin-4-ylethoxy)-4-pyridylcarbonitrile.

[0583] d) 2-(1-pyrrolidinylethoxy)-4-pyridylcarbonitrile.

[0584] e) 2-(1-methylpyrrolin-2-ylethoxy)-4-pyridylcarbonitrile.

[0585] f) 2-[2-(1-Boc-azetidin-3-yl)-ethoxy]-4-pyridylcarbonitrile.

Preparation XX-[2-(1-methylpiperidin-4-yloxy)-pyridin-4-yl]methylaminebis hydrochloride

[0586] [2-(1-Methylpiperidin-4-yloxy)-pyridin-4-yl]methylamine wasdiluted with Et₂O (50 ml) and 1M HCl/Et₂O (47 ml) was added. The vesselwas swirled until precipitate formed.

Preparation XXI-2-(2-morpholin-4-yl-ethoxy)-4-pyridylcarbonitrile

[0587] 2-(2-Morpholin-4-yl-ethoxy)-4-pyridylcarbonitrile was preparedfrom 2-chloro-4-cyanopyridine and 2-morpholin-4-yl-ethanol by aprocedure similar to that described in the preparation of2-(1-methylpiperidin-4-yloxy)-4-pyridylcarbonitrile. The HCl salt wasprepared similar to that described for[2-(1-methylpiperidin-4-yloxy)-pyridin-4-yl]methylamine bishydrochloride.

Preparation XXII-2-morpholin-4-yl-propanol

[0588] LAH powder (1.6 g) was added to a flask while under N₂atmosphere, immediately followed by THF (50 ml). The mixture was chilledto 0° C., methyl 2-morpholin-4-yl-propionate (5 g) was added dropwise tothe reaction mixture and stirred at 0° C. After 1 h, the mixture wasworked up by adding H₂O (44 mL), 2N NaOH (44 mL), then H₂O (44 mL, 3×).After 30 min of stirring, the mixture was filtered through Celite® andthe organic portion was concentrated in vacuo providing2-morpholin-4-yl-propanol as a colorless oil.

[0589] The following compounds were prepared similarly to the procedureoutlined above:

[0590] a) (1-Methyl-piperidin-4-yl)-methanol. M+H 130.2. Calc'd 129.1.

Preparation XXIII-2-(2-morpholin-4-yl-propoxy)-4-pyridylcarbonitrile

[0591] 2-(2-Morpholin-4-yl-propoxy)-4-pyridylcarbonitrile was preparedfrom 2-chloro-4-cyanopyridine and 2-morpholin-4-yl-propanol by aprocedure similar to that described in the preparation of2-(1-methylpiperidin-4-yloxy)-4-pyridylcarbonitrile.

PreparationXXIV-2-(1-Methyl-pyrrolidin-2-ylmethoxy)-4-pyridylcarbonitrile

[0592] 2-(1-Methyl-pyrrolidin-2-ylmethoxy)-4-pyridylcarbonitrile wasprepared from 2-chloro-4-cyanopyridine and1-methyl-pyrrolidin-2-ylmethanol by a procedure similar to thatdescribed in the preparation of2-(1-methylpiperidin-4-yloxy)-4-pyridylcarbonitrile. ESI MS: (M+H)=218.

Preparation XXV-2-(3-morpholin-4-yl-propylamino)-4-pyridylcarbonitrile

[0593] To a flask charged with 2-chloro-4-cyanopyridine (2.0 g), wasadded the aminopropyl morpholine (2.11 ml). The mixture was heated to79° C. for 5 h and stirred. After 5 h the reaction was incomplete. Themixture was then heated at 60° C. overnight. The crude compound waspurified on silica gel (1-5% MeOH/CH₂Cl₂ gradient). ESI MS: (M+H)=247,(M-H)=245.

Preparation XXVI-5-Nitro-2-pentafluoroethylphenol

[0594] Combined 2-methoxy-4-nitro-1-pentafluoroethylbenzene (9.35 g) andpyridine HCl in a round bottom flask and heated at 210° C. for 1 h thencooled to RT. The mixture was diluted with EtOAc and 2N HCl (>500 ml)until all residue dissolved. The organic layer was removed, washed with2N HCl (2×) and concentrated in vacuo. The residue was dissolved inhexanes and Et₂O, washed with 2N HCl, then brine. Dried organic layerover Na₂SO₄, filtered, concentrated in vacuo and dried under high vacuumto provide 5-nitro-2-pentafluoromethylphenol.

Preparation XXVII-2-tert-Butyl-5-nitro-aniline

[0595] To H₂SO₄ (98%, 389 mL) in a 500 mL 3-neck flask was added2-tert-butyl aniline (40.6 mL). The reaction was cooled to −10° C. andKNO₃ in 3.89 g aliquots was added every 6 min for a total of 10aliquots. Tried to maintain temperature at −5° C. to −10° C. After finaladdition of KNO_(3,) stirred the reaction for five min then it waspoured onto ice (50 g). The black mix was diluted with H₂O and extractedwith EtOAc. The aqueous layer was basified with solid NaOH slowly thenextracted with EtOAc (2×). The combined organic layers were washed with6N NaOH and then with a mix of 6N NaOH and brine, dried over Na₂SO₄,filtered and concentrated in vacuo to obtain crude2-tert-butyl-5-nitro-aniline as a dark red-black oil which solidifiedwhen standing at RT. The crude material was triturated with about 130 mLhexanes. After decanting the hexanes, the material was dried to obtain adark-red black solid.

Preparation XXVIII-2-tert-Butyl-5-nitrophenol

[0596] In a 250 ml round bottom flask, 20 mL concentrated H₂SO4 wasadded to 2-tert-butyl-5-nitro-aniline (7.15 g) by adding 5 mL aliquotsof acid and sonicating with occasional heating until all of the startinganiline went into solution. H₂O (84 ml) was added with stirring, thenthe reaction was cooled to 0° C. forming a yellow-orange suspension. Asolution of NaNO₂ (2.792 g) in H₂O (11.2 mL) was added dropwise to thesuspension and stirred for 5 min. Excess NaNO₂ was neutralized withurea, then the cloudy solution was transferred to 500 ml 3-necked roundbottom flask then added 17 mL of 1:2 H₂SO₄:H₂O solution, and heated atreflux. Two additional 5 mL aliquots of 1:2 H₂SO₄:H₂O solution, a 7 mLaliquot of 1:2 H₂SO₄:H₂O solution and another 10 mL of 1:2 H₂SO₄:H₂Owere added while heating at reflux. The mixture was cooled to RT forminga black layer floating on top of the aqueous layer. The black layer wasdiluted with EtOAc (300 mL) and separated. The organic layer was washedwith H20 then brine, dried over Na₂SO₄ and concentrated in vacuo. Crudeoil was purified on silica gel column with 8% EtOAc/Hexanes. Upon dryingunder vacuum, the 2-tert-butyl-5-nitrophenol was isolated as a brownsolid.

Preparation XXIX-1-methylpiperidine-4-carboxylic acid ethyl ester

[0597] Piperidine-4-carboxylic acid ethyl ester (78 g) was dissolved inMeOH (1.2 L) at RT then formaldehyde (37%, 90 ml) and acetic acid (42ml) were added and stirred for 2 h. The mixture was cooled to 0° C.,NaCNBH₃ (70 g) was added, and the mix was stirred for 20 min at 0° C.,then overnight at RT. The mixture was cooled to 0° C. then quenched with6N NaOH.

[0598] The mixture was concentrated in vacuo to an aqueous layer, whichwas extracted with EtOAc (4×), brine-washed, dried over Na₂SO₄, andconcentrated in vacuo to provide 1-methylpiperidine-4-carboxylic acidethyl ester.

[0599] The following compounds were prepared similarly to the procedureoutlined above:

[0600] a) (1-Methyl-piperidin-4-yl)-methanol. M+H 130.2. Calc'd 129.1.

PreparationXXX-N-[4-tert-Butyl-3-(1-methyl-piperidin-4-ylmethoxy)-phenyl]-2-chloro-nicotinamide

[0601]N-[4-tert-Butyl-3-(1-methyl-piperidin-4-ylmethoxy)-phenyl]-2-chloro-nicotinamidewas prepared from4-tert-butyl-3-(1-methyl-piperidin-4-ylmethoxy)-phenylamine by aprocedure similar to that described in the preparation of1-Boc-4-{3-[(2-chloro-pyridine-3-carbonyl)-amino]-5-trifluoromethyl-phenoxy}-piperidine.

Preparation XXXI-1-[2-(2-tert-Butyl-5-nitro-phenoxy)-ethyl]-piperidine

[0602] To 2-tert-butyl-5-nitrophenol (1.01 g) and K₂CO₃ (1.72 g) wasadded acetone (35 ml) and H₂O (10.5 mL), then1-(2-chloroethyl)piperidine HCl (1.909 g) and TBAI (153 mg). The mixturewas stirred at reflux overnight. Additional K₂CO3 (850 mg) and1-(2-chloroethyl)-piperidine HCl (950 mg) were added and the mixture washeated at reflux for 6 h. The mixture was concentrated in vacuo to anaqueous layer which was acidified with 2N HCl and extracted with EtOAc.The aqueous layer was basified with 6N NaOH and washed with CH₂Cl₂ (3×).The combined organic layers were washed with brine/1N NaOH and driedover Na₂SO₄. Washed the EtOAc layer with 2N NaOH/brine and dried overNa₂SO₄. The crude material was purified by silica gel columnchromatography with 15% EtOAc/Hexanes to yield1-[2-(2-tert-butyl-5-nitro-phenoxy)-ethyl]-piperidine as a light tansolid. (M+1)=307.3.

Preparation XXXII-1-Boc-Piperidine-4-carboxylic acid ethyl ester

[0603] To a stirred solution of piperidine-4-carboxylic acid ethyl ester(23.5 g) in EtOAc (118 ml) at 0° C. was added dropwise Boc₂O in EtOAc(60 ml). The reaction was warmed to RT and stirred overnight. Washedreaction with H₂O, 0.1N HCl, H₂O, NaHCO₃ and brine. The organic layerwas dried over Na₂SO₄, filtered and concentrated in vacuo. The liquidwas dried under vacuum to provide 1-Boc-piperidine-4-carboxylic acidethyl ester.

[0604] The following compounds were prepared similarly to the procedureoutlined above:

[0605] a) N-Boc-(2-chloropyrimidin-4-yl)-methylamine.

[0606] b) 1-(2-tert-Butyl-4-nitrophenyl)-4-Boc-piperazine.

[0607] c) 1-Boc-azetidine-3-carboxylic acid

[0608] d) 1-Boc-4-Hydroxymethyl-piperidine using TEA.

Preparation XXXIII-1-Boc-4-hydroxymethyl-piperidine

[0609] 1-Boc-4-Hydroxymethyl-piperidine was prepared from1-Boc-piperidine-4-carboxylic acid ethyl ester by a procedure similar tothat described in the preparation of 2-morpholin-4-yl-propanol.

Preparation XXXIV-1-Boc-4-Methylsulfonyloxymethyl-piperidine

[0610] Dissolved 1-Boc-4-hydroxymethyl-piperidine in anhydrous CH₂Cl₂(50 ml) and TEA (4.5 ml) and cooled to 0° C. Mesyl chloride (840 μl) wasadded and the mixture was stirred for 15 min then at RT for 45 min. Themixture was washed with brine/1N HCl and then brine, dried over Na₂SO₄,concentrated in vacuo and dried under high vacuum to provide1-Boc-4-methylsulfonyloxymethyl-piperidine as a yellow orange thick oil.

[0611] The following compounds were prepared similarly to the procedureoutlined above:

[0612] a) 1-Boc-3-methylsulfonyloxymethyl-azetidine.

PreparationXXXV-1-Boc-4-(3-nitro-6-pentafluoroethyl-phenoxymethyl)-piperidine

[0613] To a slurry of 60% NaH suspension in DMF (30 mL) at RT added asolution of 5-nitro-2-pentafluoroethyl-phenol (3.6 g) in 5 mL DMF. Thedark red mixture was stirred at RT for 10 min then added a solution of1-Boc-4-methylsulfonyloxymethyl-piperidine (3.1 g) in 5 mL DMF. Thereaction was stirred at 60° C. and 95° C. After 1 h, added 2.94 g K₂CO₃and stirred overnight at 105° C . After cooling to RT, the reaction wasdiluted with hexanes and 1N NaOH. Separated layers, and washed organiclayer with iN NaOH and with brine, dried over Na₂SO₄, filtered andconcentrated in vacuo. Purification with silica gel columnchromatography with 8% EtOAc/Hexanes yielded1-Boc-4-(3-nitro-6-pentafluoroethyl-phenoxymethyl)-piperidine as a lightyellow thick oil.

PreparationXXXVI-4-(3-nitro-6-pentafluoroethyl-phenoxymethyl)-piperidine

[0614] 4-(3-Nitro-6-pentafluoroethyl-phenoxymethyl)-piperidine wasprepared from1-Boc-4-(3-nitro-6-pentafluoroethyl-phenoxymethyl)-piperidine by aprocedure similar to that described in the preparation of2-(3-nitro-5-trifluoromethyl-phenoxymethyl)-pyrrolidine.

PreparationXXXVII-1-methyl-4-(3-nitro-6-pentafluoroethyl-phenoxymethyl)-piperidine

[0615] 4-(3-Nitro-6-pentafluoroethyl-phenoxymethyl)-piperidine (316.5mg) was dissolved in 2.7 mL CH3CN, then added 37% formaldehyde/H₂O (360ul) and then NaBH₃CN (90 mg). Upon addition of NaCNBH₃ the reactionexothermed slightly. The reaction was stirred at RT and pH wasmaintained at ˜7 by addition of drops of glacial AcOH. After about 1 h,the mixture was concentrated in vacua, treated with 8 mL 2N KOH andextracted two times with 10 mL Et₂O. The organic layers were washed with0.5N KOH and then the combined organic layers were extracted two timeswith 1N HCl. The aqueous layer was basified with solid KOH and extractedtwo times with Et₂O. This organic layer was then washed with brine/1NNaOH, dried over Na₂SO₄, filtered, concentrated in vacua and dried underhigh vacuum to give pure compound.

PreparationXXXVIII-1-Isopropyl-4-(5-nitro-2-pentafluoroethyl-phenoxymethyl)-piperidine

[0616] Dissolved 4-(5-nitro-2-pentafluoroethyl-phenoxymethyl)-piperidine(646 mg) in 1,2-dichloroethane (6.4 ml), then added acetone (136 ul),NaBH(OAc)₃ (541 mg) and finally AcOH (105 ul). Stirred the cloudy yellowsolution under N₂ at RT overnight. Added another 130 uL acetone andstirred at RT over weekend. Quenched the reaction with 30 mL N NaOH/H₂Oand stirred 10 min. Extracted with Et₂O and the organic layer wasbrine-washed, dried over Na₂SO₄, filtered and concentrated in vacuo.Dried under high vacuum for several h to obtain1-isopropyl-4-(5-nitro-2-pentafluoroethyl-phenoxymethyl)-piperidine as ayellow orange solid.

[0617] The following compounds were prepared similarly to the procedureoutlined above:

[0618] a)3,3-Dimethyl-1-(1-methyl-piperidin-4-yl)-6-nitro-2,3-dihydro-1H-indolewas prepared using 1-methyl-piperidin-4-one. M+H 290; Calc'd 289.4.

[0619] b)3,3-Dimethyl-1-(1-Boc-piperidin-4-ylmethyl)-6-nitro-2,3-dihydro-1H-indoleusing 1-Boc-4-formyl-piperidine.

PreparationXXXIX-3,3-Dimethyl-1-(1-methyl-piperidin-4-ylmethyl)-6-nitro-2,3-dihydro-1H-indole:

[0620] 3,3-Dimethyl-1-piperidin-4-ylmethyl-6-nitro-2,3-dihydro-1H-indolewas treated with an excess of formaldehyde and NaBH(OAc)₃ and stirredovernight at RT. The reaction was quenched with MeOH and concentrated invacuo. The residue was partitioned between EtOAc and 1N NaOH. Theorganic layer was removed, washed with brine, dried (Na₂SO₄), filteredand concentrated to provide the compound.

Preparation XL-(S) 2-(5-Nitro-2-pentafluoroethyl-phenoxymethyl)-oxirane:

[0621] Combined 5-nitro-2-pentafluoromethylphenol (2.69 g), DMF (25 ml)K₂CO₃ (3.03 g) and (S) toluene-4-sulfonic acid oxiranyl-methyl ester(2.27 g) and stirred the mixture at 90° C. After about 4 h, the mix wascooled, diluted with EtOAc, washed with H₂O, 1N NaOH (2×), 1N HCl andthen with brine. Dried over Na₂SO₄, filtered and concentrated in vacuo.Purified the crude on silica gel column with 5% EtOAc/hexane and dryingunder high vacuum provided the(S)-2-(5-nitro-2-pentafluoroethyl-phenoxymethyl)-oxirane.

[0622] The following compounds were prepared similarly to the procedureoutlined above:

[0623] a) (R)-2-(5-Nitro-2-pentafluoroethyl-phenoxymethyl)-oxirane.

Preparation XLI-(S)2-Chloro-N-[3-(2-hydroxy-3-pyrrolidin-1-yl-propoxy)-4-pentafluoroethyl-phenyl]-nicotinamide

[0624] (S)2-Chloro-N-[4-(2-oxiranylmethoxy-)-3-pentafluoroethyl-phenyl]-nicotinamide(1.11 g) in a sealed tube and added pyrrolidine (285 μl). Stirred aftersealing tube at 60° C. After 12 h, the mix was concentrated in vacuo andpurified on a silica gel column (5:95:0.5 MeOH:CH₂Cl₂:NH₄OH-8:92:1,MeOH:CH₂Cl₂:NH₄OH). Concentrated in vacuo and dried under high vacuum toobtain pure compound.

[0625] The following compounds were prepared similarly to the procedureoutlined above:

[0626] a) (R)1-(5-Nitro-2-pentafluoroethyl-phenoxy)-3-pyrrolidin-1-yl-propan-2-ol.

Preparation XLII-5-nitro-2-trifluoromethylanisole

[0627] Cooled 140 mL pyridine in a large sealable vessel to −40° C.Bubbled in trifluoromethyl iodide from a gas cylinder which had beenkept in freezer overnight. After adding ICF₃ for 20 min, added2-iodo-5-nitroanisole (24.63 g) and copper powder (67.25 g). Sealedvessel and stirred vigorously for 22 h at 140° C. After cooling to −50°C., carefully unsealed reaction vessel and poured onto ice and Et₂O.Repeatedly washed with Et₂O and H₂O. Allowed the ice—Et₂O mixture towarm to RT. Separated layers, washed organic layer with 1N HCl (3×),then brine, dried over Na₂SO₄, filtered and concentrated in vacuo.Eluted material through silica gel plug (4.5:1 Hex:CH₂Cl₂) to provide5-nitro-2-trifluoromethylanisole.

PreparationXLIII-1-[2-(5-nitro-2-trifluoromethylphenoxy)ethyl]pyrrolidine

[0628] 1-[2-(5-Nitro-2-trifluoromethylphenoxy)ethyl]-pyrrolidine wasprepared from 5-nitro-2-trifluoromethyl-phenol and1-(2-chloroethyl)pyrrolidine by a procedure similar to that describedfor 1-[2-(2-tert-butyl-5-nitro-phenoxy)-ethyl]-piperidine.

PreparationXLIV-1-[2-(5-Nitro-2-pentafluoroethyl-phenoxy)-ethyl]-piperidine

[0629] 1-[2-(5-Nitro-2-pentafluoroethyl-phenoxy)-ethyl]-piperidine wasprepared from 5-nitro-2-pentafluoroethylphenol and1-(2-chloroethyl)piperidine by a procedure similar to that described inthe preparation of1-[2-(2-tert-butyl-5-nitro-phenoxy)-ethyl]-piperidine.

PreparationXLV-3-(1-Boc-pyrrolidin-2-ylmethoxy)-4-pentafluoroethyl-phenylamine

[0630] 3-(2-Pyrrolidin-1-yl-methoxy)-4-trifluoromethyl-phenylamine wasprepared from 1-[2-(5-nitro-2-trifluoromethylphenoxy)methyl]-pyrrolidineby a procedure similar to that described in the preparation of1-Boc-4-(3-amino-5-trifluoromethyl-phenoxy)-piperidine.

PreparationXLVI-2-Chloro-N-[3-(2-pyrrolidin-1-yl-ethoxy)-4-trifluoromethyl-phenyl]-nicotinamide

[0631]2-Chloro-N-[3-(2-pyrrolidin-1-yl-ethoxy)-4-trifluoromethyl-phenyl]-nicotinamidewas prepared from3-(2-pyrrolidin-1-yl-ethoxy)-4-trifluoromethyl-phenylamine and2-chloropyridine-3-carbonyl chloride by a procedure similar to thatdescribed in the preparation of1-Boc-4-{3-[(2-chloro-pyridine-3-carbonyl)-amino]-5-trifluoromethyl-phenoxy}-piperidine.

Preparation XLVII-(R) Acetic acid2-(5-nitro-2-pentafluoroethyl-phenoxy)-1-pyrrolidin-1-ylmethyl-ethylester

[0632] Dissolved1-(5-nitro-2-pentafluoroethyl-phenoxy)-3-pyrrolidin-1-yl-propan-2-ol(3.5 g) in CH₂Cl₂ (15 ml) added TEA (2.55 ml) and cooled to 0° C. Acetylchloride (781.3 μl) was added dropwise, forming a suspension. Themixture was warmed to RT and stirred for 1.5 h. Additional acetylchloride (200 μl) was added and the mix was stirred for another h. Themixture was diluted with CH₂Cl₂ and washed with sat. NaHCO₃. The organiclayer was removed, washed with brine and back extracted with CH₂Cl₂.Dried the combined organic layers over Na₂SO₄, filtered and concentratedin vacuo. The residue was purified over silica gel column (5:94.5:0.5MeOH:CH₂Cl₂:NH₄OH) to provide acetic acid2-(5-nitro-2-pentafluoroethyl-phenoxy)-1-pyrrolidin-1-ylmethyl-ethylester as a yellow brown oil.

[0633] The following compounds were prepared similarly to the procedureoutlined above:

[0634] a) (R) Acetic acid2-(5-amino-2-pentafluoroethyl-phenoxy)-1-pyrrolidin-1-yl-methyl-ethylester.

[0635] b)1-(2,2-Dimethyl-6-nitro-2,3-dihydro-benzo[1,4]oxazin-4-yl)-ethanone.M-NO₂ 206.4; Calc'd 250.1.

Preparation XLVIII-(R)2-Chloro-N-[3-(2-hydroxy-2-pyrrolidin-1-yl-propoxy)-4-pentafluoroethyl-phenyl]-nicotinamide

[0636] (R) Acetic acid2-{5-[(2-chloro-pyridine-3-carbonyl)-amino]-2-pentafluoroethyl-phenoxy}-1-pyrrolidin-1-yl-ethylester (408 mg) was dissolved in MeOH (15 ml) and NH₄OH (6 ml) was addedand the mixture was stirred at RT for 6 h. The reaction was concentratedin vacuo and dried under high vacuum. The residue was purified oversilica gel column (8:92:0.6 MeOH:CH₂Cl₂:NH₄OH). The purified fractionswere concentrated in vacuo and dried again to provide(R)-2-chloro-N-[3-(2-hydroxy-2-pyrrolidin-1-yl-ethoxy)-4-pentafluoroethyl-phenyl]-nicotinamideas a white foam.

PreparationXLIX-2-Dimethylamino-1-(3,3-dimethyl-6-nitro-2,3-dihydro-indol-1-yl)-ethanone

[0637] 3,3-Dimethyl-6-nitro-2,3-dihydro-1H-indole (5 g) was dissolved inDMF (100 ml) and HOAt (3.89 g) dimethylamino-acetic acid (5.83 g) andEDC (3.89 g) were added. The reaction was stirred overnight. The mixturewas diluted with CH₂Cl₂ (1L) and washed with sat'd NaHCO₃ (3×200 ml).The organic layer was washed with brine, dried over Na₂SO₄, filtered andconcentrated in vacuo. The residue was purified by flash chromatography(SiO₂, EtOAc to 5% MeOH/EtOAc) to afford the title compound.

[0638] The following compounds were prepared similarly to the procedureoutlined above:

[0639] a)1-(3,3-Dimethyl-6-nitro-2,3-dihydro-indol-1-yl)-2-(N-Boc-amino)-ethanone.

PreparationL-1-(6-Amino-3,3-dimethyl-2,3-dihydro-indol-1-yl)-2-(N-Boc-amino)-ethanone

[0640]1-(3,3-Dimethyl-6-nitro-2,3-dihydro-indol-1-yl)-2-(N-Boc-amino)-ethanone(3.9 g) was dissolved in EtOH (30 ml) and Fe powder (3.1 g) NH₄Cl (299mg) and H₂O (5 ml) were added. The reaction was stirred at 80° C.overnight. The reaction was filtered through Celite® and evaporated offthe MeOH. The residue was partitioned between CH₂Cl₂ and sat'd NaHCO₃.The organic layer was removed, washed with brine, dried over Na₂SO₄,filtered and concentrated in vacuo. The residue was purified by flashchromatography (SiO₂, 25% EtOAc/hexane). The purified fractions wereconcentrated in vacuo to afford the compound as a white powder.

[0641] The following compounds were prepared similarly to the procedureoutlined above:

[0642] a)1-(6-Amino-3,3-dimethyl-2,3-dihydro-indol-1-yl)-2-dimethylamino-ethanone.

[0643] b)3,3-Dimethyl-1-(1-methyl-piperidin-4-ylmethyl)-2,3-dihydro-1H-indol-6-ylamine.

[0644] c)3-(4-Methyl-piperazin-1-ylmethyl)-4-pentafluoroethyl-phenylamine. M+H324.2. Calc'd 323.

[0645] d)3,3-Dimethyl-1-(1-methyl-piperidin-4-yl)-2,3-dihydro-1H-indol-6-ylamine.M+H 259.6; Calc'd 259.3.

[0646] e)3,3-Dimethyl-1,1-dioxo-2,3-dihydro-1H-116-benzo[d]isothiazol-6-ylamine

[0647] f) 1,1,4,4-Tetramethyl-1,2,3,4-tetrahydro-naphth-6-ylamine.

[0648] g)3,3-Dimethyl-1-(1-Boc-piperidin-4-ylmethyl)-2,3-dihydro-1H-indol-6-ylamine.

PreparationLI-2-Boc-4,4-dimethyl-7-nitro-1,2,3,4-tetrahydro-isoquinoline:

[0649] 4,4-Dimethyl-7-nitro-1,2,3,4-tetrahydro-isoquinoline (150 mg) wasdissolved with CH₂Cl₂ (3 ml) DIEA (100 ul) DMAP (208 mg and Boc₂O (204mg) and the mixture was stirred for 6 h at RT. The reaction was dilutedwith CH₂Cl₂, washed with sat'd NaHCO₃ and dried over MgSO₄, filtered andconcentrated to provide the compound which was used without furtherpurification.

[0650] The following compounds were prepared similarly to the procedureoutlined above substituting Ac₂O:

[0651] a)1-(4,4-Dimethyl-7-nitro-3,4-dihydro-1H-isoquinolin-2-yl)-ethanone. M+H249.3.

Preparation LII-2-Bromo-N-(4-methoxy-benzyl)-5-nitro-benzamide

[0652] PMB-amine (5.35 ml) in CH₂Cl₂ (130 ml) was slowly added to2-bromo-5-nitro-benzoyl chloride (10.55 g) and NaHCO₃ (9.6 g) and themixture was stirred at RT for 1 h. The mixture was diluted with CH₂Cl₂(1 L), filtered, washed with dilute HCl, dried, filtered again,concentrated and dried under vacuum to provide the compound as a whitesolid. M+H 367. Calc'd 366.

PreparationLIII-2-Bromo-N-(4-methoxy-benzyl)-N-(2-methyl-allyl)-5-nitro-benzamide

[0653] To a suspension of NaH (1.22 g) in DMF (130 ml) was added2-bromo-N-(4-methoxy-benzyl)-5-nitro-benzamide (6.2 g) in DMF (60 ml) at−78 C. The mixture was warmed to 0° C., 3-bromo-2-methyl-propene (4.57g) was added and the mixture was stirred for 2 h at 0° C. The reactionwas poured into ice H₂O, extracted with EtOAc (2×400 ml), dried overMgSO₄, filtered and concentrated to a DMF solution which was usedwithout further purification.

Preparation LIV-of2-(4-Methoxy-benzyl)-4,4-dimethyl-7-nitro-3,4-dihydro-2H-isoquinolin-1-one

[0654] 2-Bromo-N-(4-methoxy-benzyl)-N-(2-methyl-allyl)-5-nitro-benzamide(23.4 mmol) was dissolved in DMF (150 ml) and Et₄NCl (4.25 g), HCO₂Na(1.75 g) and NaOAc (4.99 g) were added. N₂ was bubbled through thesolution for 10 min, then Pd(OAc)₂ (490 mg) was added and the mixturewas stirred overnight at 70° C. The mixture was extracted with EtOAc,washed with sat'd NH₄Cl, dried over MgSO₄, filtered and concentrateduntil the compound precipitated as a white solid.

[0655] The following compounds were prepared similarly to the procedureoutlined above:

[0656] a) 3,3-Dimethyl-6-nitro-2,3-dihydro-benzofuran was prepared from1-bromo-2-(2-methyl-allyloxy)-4-nitro-benzene.

[0657] b) 3,9,9-Trimethyl-6-nitro-4,9-dihydro-3H-3-aza-fluorene wasprepared from4-[1-(2-bromo-4-nitro-phenyl)-1-methyl-ethyl]-1-methyl-1,2,3,6-tetrahydro-pyridine.

Preparation LV-4,4-Dimethyl-7-nitro-3,4-dihydro-2H-isoquinolin-1-one

[0658]2-(4-Methoxy-benzyl)-4,4-dimethyl-7-nitro-3,4-dihydro-2H-isoquinolin-1-one(2.0 g) was dissolved in CH₃CN (100 ml) and H₂O (50 ml) and cooled to 0°C. CAN (9.64 g) was added and the reaction was stirred at 0° C. for 30min, then warmed to RT and stirred for 6 h. The mixture was extractedwith CH₂Cl₂ (2×300 ml) washed with sat'd NH₄Cl, dried over MgSO₄,filtered and concentrated. The crude material was recrystallized inCH₂Cl₂/EtOAc (1:1) to give4,4-dimethyl-7-nitro-3,4-dihydro-2H-isoquinolin-1-one as a white solid.

Preparation LVI-4,4-Dimethyl-7-nitro-1,2,3,4-tetrahydro-isoquinoline

[0659] 4,4-Dimethyl-7-nitro-3,4-dihydro-2H-isoquinolin-1-one (230 mg)was dissolved in THF (10 ml) and BH₃Me₂S (400 ul) was added and thereaction was stirred overnight at RT. The reaction was quenched withMeOH (10 ml) and NaOH (200 mg) and heating at reflux for 20 min. Themixture was extracted with EtOAc, washed with sat'd NH₄Cl, extractedwith 10% HCl (20 ml). The acidic solution was treated with 5N NaOH (15ml), extracted with EtOAc (30 ml) dried, filtered and evaporated to givethe compound as a yellow solid. M+H 207.2, Calc'd 206.

[0660] The following compounds were prepared similarly to the procedureoutlined above:

[0661] a) 4-Boc-2,2-dimethyl-6-nitro-3,4-dihydro-2H-benzo[1,4]oxazine.

Preparation LVII-2-Bromomethyl-4-nitro-1-pentafluoroethyl-benzene

[0662] 2-Methyl-4-nitro-1-pentafluoroethyl-benzene (2.55 g) wasdissolved in CCl₄ (30 ml) and AIBN (164 mg) and NBS (1.96 g) were added.The reaction was heated to reflux and stirred for 24 h. The mix wasdiluted with CH₂Cl₂, washed with sat'd NaHCO₃, dried over MgSO₄ andconcentrated to give the compound as an oil which was used withoutfurther purification.

PreparationLVIII-1-Methyl-4-(5-nitro-2-pentafluoroethyl-benzyl)-piperazine

[0663] 2-Bromomethyl-4-nitro-1-pentafluoroethyl-benzene (2.6 g) wasadded to N-methylpiperazine (5 ml) and stirred at RT for 3 h. Themixture was filtered and the filtrate was treated with 1-chlorobutane,extracted with 2N HCl (100 ml). The acidic solution was treated with 5NNaOH (6 ml) then extracted with EtOAc. The organic layer was removed,dried over MgSO₄ and concentrated to give the compound as an oil.

[0664] The following compounds were prepared similarly to the procedureoutlined above:

[0665] a) 4-(5-Nitro-2-pentafluoroethyl-benzyl)-morpholine.

Preparation LIX-1-Boc-4-(5-nitro-2-pentafluoroethyl-benzyl)-piperazine

[0666] 2-Bromomethyl-4-nitro-1-pentafluoroethyl-benzene (2.5 g) wasdissolved in CH₂Cl₂ and added to N-Boc-piperazine (2.5 g) and NaHCO₃ (1g) and stirred at RT overnight. The mixture was diluted with CH₂Cl₂ (100ml), washed with sat'd NH₄Cl, dried over MgSO₄, filtered andconcentrated. The residue was purified by silica gel chromatography(hexane, CH₂Cl₂:hexane 2:8) to give the compound as an yellow solid.

PreparationLX-(4-Boc-piperazin-1-yl)-(3-nitro-5-trifluoromethyl-phenyl)-methanone

[0667] A mixture of 3-nitro-5-trifluoromethyl-benzoic acid (4.13 g),4-Boc-piperazine (2.97 g), EDC (3.88 g), HOBt (2.74 g), DIEA (3.33 ml)in CH₂Cl₂ (120 ml) was stirred at RT for 3 h. The mixture was dilutedwith CH₂Cl₂ (100 ml), washed with sat'd NH₄Cl, dried over MgSO₄,filtered and concentrated. The residue was purified by silica gelchromatography (hexane, CH₂Cl₂:hexane 1:2) to give the compound as awhite solid.

Preparation LXI-1-Boc-4-(3-nitro-5-trifluoromethyl-benzyl)-piperazine

[0668](4-Boc-piperazin-1-yl)-(3-nitro-5-trifluoromethyl-phenyl)-methanone (403mg) was dissolved in THF (6 ml) and BH₃Me₂S (300 gl) was added and thereaction was stirred for 3 h at 60° C. and 2 h at RT. The reaction wasquenched with MeOH (5 ml) and NaOH (100 mg) and stirred at RT for 1 h.The mixture was concentrated and dissolved in CH₂Cl₂, washed with sat'dNH₄Cl/NaHCO₃, dried (MgSO₄), filtered and evaporated to give thecompound as an oil. M+H 390.3.

Preparation LXII-2-Ethyl-4-aminomethyl pyridine:

[0669] To a solution of 2-ethyl-4-thiopyridylamide (10 g) in MeOH (250ml) was added Raney 2800 Nickel (5 g, Aldrich) in one portion. Themixture was stirred at RT for 2 days then at 60° C. for 16 h. Themixture was filtered, concentrated to provide the desired compound.

PreparationLXIII-N-Boc-[2-(4-morpholin-4-yl-butyl)-pyrimidin-4-ylmethyl]-amine

[0670] N-Boc-(2-chloropyrimidine)-methylamine (663 mg) and4-(aminopropyl)morpholine (786 mg) were dissolved in MEOH andconcentrated in vacuo. The residue was heated at 100° C. for 15 min,forming a solid which was dissolved in CH₂Cl₂/MeOH then concentratedagain and heated 15 min more. Concentrated in vacuo and dried under highvacuum. Triturated with a small amount of IpOH and allowed to settleover a weekend. Filtered, rinsing with a small amount of IpOH to providethe compound as a white solid.

[0671] The following compounds were prepared similarly to the procedureoutlined above:

[0672] a)(4-Bocaminomethyl-pyrimidin-2-yl)-[2-(1-methyl-pyrrolidin-2-yl)-ethyl]-amine.M+H 336.5; Calc'd 335.45.

Preparation LXIV -2-fluoronicotinic acid

[0673] In a flame dried 3-necked round bottom flask equipped with adropping funnel and thermometer, under N₂, THF (250 ml) was added viacannula. LDA (2M in cyclohexane, 54 ml) was added via cannula as theflask was cooled to −78° C. At −78° C., 2-fluoropyridine (8.87 ml) wasadded dropwise over 10 min. The reaction was stirred for 3 h.Condensation was blown off (with N₂) a few cubes of solid CO₂ and theywere added to the mixture. The mixture was warmed to RT once thesolution turned yellow, and it was stirred overnight. The reaction wascooled to 0° C. and the pH was adjusted to −2.5 with 5N HCl. The mixturewas concentrated in vacuo and extracted with EtOAc. The EtOAc layer waswashed with brine, dried over MgSO₄, filtered and concentrated todryness. The resulting solid was slurried in EtOAc (100 ml), filtered,washed with cold EtOAc and dried at 50° C. for 1 h to afford2-fluoronictinic acid. M+H 142.1; Calc'd 141.0.

Preparation LXV-4-cyano-2-methoxypyridine

[0674] Under a stream of N₂ and with cooling, Na metal (2.7 g) was addedto MeOH (36 ml) with a considerable exotherm. After the Na is dissolved,a solution of 2-chloro-4-cyanopyridine (15 g) in dioxane:MeOH (1:1, 110ml) was added via dropping funnel over a 10 min period. The reaction washeated to reflux for 3.5 h then cooled at ˜10° C. overnight. Solid wasfiltered off and the solid was washed with MeOH. The filtrate wasconcentrated to ˜60 ml and H₂O (60 ml) was added to redissolve aprecipitate. Upon further concentration, a precipitate formed which waswashed with H₂O. Further concentration produced additional solids. Thesolids were combined and dried in vacuo overnight at 35° C. to provide4-cyano-2-methoxypyridine which was used as is.

Preparation LXVI-(2-methoxypyridin-4-yl)methylamine

[0675] 4-Cyano-2-methoxypyridine (1.7 g) was dissolved in MeOH (50 ml)and conc. HCl (4.96 ml) was added. Pd/C (10%) was added and H₂ was addedand let stand overnight. The solids were filtered through Celite® andthe cake was washed with MeOH (˜250 ml). Concentration in vacuo producedan oil which was dissolved in MeOH (˜20 ml). Et₂O (200 ml) was added andstirred for 1 h. The resulting precipitate was filtered and washed withEt₂O to afford (2-methoxypyridin-4-yl)methylamine (HCl salt) as anoff-white solid.

Preparation LXVII-2-(4-Amino-phenyl)-2-methyl-propionic acid methylester

[0676] 2-Methyl-2-(4-nitro-phenyl)-propionic acid methyl ester (2.1 g)was dissolved in THF (70 ml) and AcOH (5 ml) and Zn (10 g) were added.The mixture was stirred for 1 h and filtered through Celite®. Thefiltrate was rinsed with EtOAc and the organics were evaporated to aresidue which was purified on silica gel chromatography (40%EtOAc/hexanes) to provide the desired compound as a yellow oil. M+H 194.

Preparation LXVIII-1-(2-tert-Butyl-phenyl)-4-methyl-piperazine

[0677] 2-tert-Butyl-phenylamine and bis-(2-chloro-ethyl)-methylaminewere mixed together with K₂CO₃ (25 g), NaI (10 g) and diglyme (250 mL)and heated at 170° C. for 8 h. Cooled and filtered solid and evaporatedsolvent. Diluted with EtOAc, washed with NaHCO₃ solution, extractedtwice more with EtOAc, washed with brine, dried over Na₂SO₄ andevaporated to give the compound as a dark solid.

[0678] The following compounds were prepared similarly to the procedureoutlined above:

[0679] a) 1-Bromo-2-(2-methyl-allyloxy)-4-nitro-benzene was preparedfrom methallyl bromide.

Preparation LXIX3-(1-Methyl-1,2,3,6-tetrahydro-pyridin-4-yl)-5-trifluoromethyl-phenylamine

[0680]3-(5,5-Dimethyl-[1,3,2]dioxaborinan-2-yl)-5-trifluoromethyl-phenylamine(8.8 g, 0.032 mol)was added to trifluoro-methanesulfonic acid1-methyl-1,2,3,6-tetrahydro-pyridin-4-yl ester (7.91 g, 0.032 mol) and2N Na₂CO₃ aqueous solution (25 mL) was bubbled through N₂ for 5 min.Pd(PPh₃)₄ (3.7 g, 3.2 mmol) was added and the reaction was heated to 80°C. for 16 h. The reaction was cooled to RT and diluted with Et₂O (100mL). The mixture was filtered through Celite® and the filtrate waswashed with NaHCO₃ aqueous solution (25 ml) followed by brine (25 mL).The organic phase was dried over Na₂SO₄ and concentrated in vacuo. Thedesired compound was isolated by passing through silica gel columnchromatography (EtOAc, then (2M NH₃) in MeOH/EtOAc) to provide a yellowoil.

Preparation LXX-3,3-Dimethyl-6-nitro-2,3-dihydro-benzo[d]isothiazole1,1-dioxide

[0681] 3,3-Dimethyl-2,3-dihydro-benzo[d]isothiazole 1,1-dioxide wasadded to KNO₃ in H₂SO₄ cooled to 0° C. and stirred for 15 min. Thereaction was warmed to RT and stirred overnight. The mix was poured intoice and extracted with EtOAc (3×), washed with H₂O and brine, dried andevaporated to give the compound which was used without furtherpurification.

[0682] The following compounds were prepared similarly to the procedureoutlined above:

[0683] a) 1,1,4,4-Tetramethyl-6-nitro-1,2,3,4-tetrahydro-naphthalene

PreparationLXXI-3-(1-Methyl-1,2,3,4-tetrahydro-pyridin-4-yl)-5-trifluoromethyl-phenylamine

[0684]3-(5,5-Dimethyl-[1,3,2]dioxaborinan-2-yl)-5-trifluoromethyl-phenylamine(1.2 g) was added to trifluoro-methanesulfonic acid1-methyl-1,2,3,6-tetrahydro-pyridin-4-yl ester (1.0 g), LiCl (500 mg,Aldrich), PPh₃ (300 mg, Aldrich) and 2M Na₂CO₃ aqueous solution (6 ml)and was bubbled with N₂ for 5 min. Pd(PPH₃)₄ (300 mg, Aldrich) was addedand the reaction was heated to 80° C. for 16 h. The reaction was cooledto RT and diluted with Et₂O (100 mL). The mixture was filtered throughCelite® and the filtrate was washed with NaHCO₃ aqueous solution (25 ml)followed by brine (25 mL). The organic phase was dried over Na₂SO₄ andconcentrated in vacuo. The desired compound was isolated by silica gelcolumn chromatography (EtOAc 10% (2M NH₃) in MeOH/EtOAc) to provideyellow oil. M+H 257.2; Calc'd 256.1.

Preparation LXXII-Trifluoromethylsulfonic acid1-methyl-1,2,3,6-tetrahydro-pyridin-4-yl ester:

[0685] In a three-necked round bottom flask equipped with a thermometerand an additional funnel was placed anhydrous THF (200 mL) and 2M LDA(82.8 mL). The solution was cooled to −78° C. and a solution of1-methyl-piperidin-4-one (20 mL) in anhydrous THF (70 mL) was addeddrop-wise. The reaction was warmed to −10° C. over 30 min and cooleddown again to −78° C. Tf₂NPh (54.32 g) in 200 mL of anhydrous THF wasadded through the additional funnel over 30 min and anhydrous THF (30mL) was added to rinse the funnel. The reaction was warmed to RT and thereaction solution was concentrated in vacuo. The residue was dissolvedin Et₂O purified on neutral Al₂O₃ column chromatography (Et₂O aselutant). The compound was obtained as orange oil. (20 g)

PreparationLXXIII-3-(5,5-Dimethyl-[1,3,2]dioxaborinan-2-yl)-5-trifluoromethyl-phenylamine

[0686] N₂ was bubbled through a solution of3-bromo-5-trifluoromethyl-phenylamine (2.38 g),5,5,5′,5′-tetramethyl-[2,2′]bi[[1,3,2]dioxaborinanyl] (2.24 g, FrontierScientific) and KOAc (2.92 g), dppf (165 mg, Aldrich) in anhydrousdioxane (50 ml) for 2 min. PdCl₂ (dppf) (243 mg, Aldrich) was added andthe reaction was heated to 80° C. for 4 h. After cooling to RT, the mixwas diluted with 50 mL of Et₂O, filtered through Celite®, and thefiltrate was concentrated in vacuo. The residue was dissolved in Et₂O(100 mL), washed with sat. NaHCO₃ aqueous solution (50 mL) followed bybrine (50 mL). The organic phase was dried over Na₂SO₄ and concentratedin vacuo. The residue was dissolved in 3:2 Et₂O/Hex (100 mL), filteredthrough Celite® and the filtrate was concentrated in vacuo to afford adark brown semi-solid.

Preparation LXXIV -1-Boc-3-Hydroxymethyl-azetidine

[0687] A solution of 1-Boc-azetidine-3-carboxylic acid (1.6 g) and Et₃N(2 ml) in anhydrous THF (60 ml) was cooled to 0° C. Isopropylchloroformate (1.3 g) was added via a syringe slowly; forming a whiteprecipitate almost immediately. The reaction was stirred for 1 h at 0°C. and the precipitate was filtered out. The filtrate was cooled to 0°C. again and aqueous NaBH₄ solution (900 mg, 5 ml) was added via pipetteand stirred for 1 h. The reaction was quenched with NaHCO₃ solution (50mL) and the compound was extracted with EtOAc (200 mL). The organicphase was washed with brine (50 mL), dried over Na₂SO₄ and concentratedin vacuo. The residue was dissolved in EtOAc and passed through a shortsilica gel pad. Concentrating the filtrate in vacuo provided thecompound as a light yellow oil.

PreparationLXXV-1-Boc-3-(3-nitro-5-trifluoromethyl-phenoxymethyl)-azetidine

[0688] A mixture of 1-Boc-3-methylsulfonyloxymethyl-azetidine (1.47 g),3-nitro-5-trifluoromethyl-phenol (1.15 g) and K₂CO₃ (1.15 g) in DMF (20ml) at 80° C. was stirred overnight. The reaction was cooled to RT anddiluted with 25 mL of sat. NaHCO₃ and 50 mL of EtOAc. The organic phasewas separated and washed with brine (25 mL), dried over Na₂SO₄ andconcentrated in vacuo. The crude compound was purified by columnchromatography (50% EtOAc/hex).

Preparation LXXVI-2,2-Dimethyl-6-nitro-3,4-dihydro-2H-benzo[1,4]oxazine

[0689] 2,2-Dimethyl-6-nitro-4H-benzo[1,4]oxazin-3-one was added toBH₃-THF complex (Aldrich) in THF with ice cooling. The mixture washeated to reflux for 2 h then carefully diluted with 12 mL of MeOH andheated to reflux for an additional 1 h. Concentrated HCl (12 mL) wasadded and heated to reflux for 1 h. The mixture was concentrated and theresulting solid was suspended in a dilute aqueous solution of NaOH (1 M)and extracted with EtOAc (100 mL×4). The organic layers were washed withH₂O and dried over MgSO₄. Evaporation of solvent gave a yellow solid.

Preparation LXXVII-2,2,4-Trimethyl-6-nitro-4H-benzo[1,4]oxazin-3-one

[0690] 2,2-Dimethyl-6-nitro-4H-benzo[1,4]oxazin-3-one (1.1 g) was mixedwith MeI (850 mg, Aldrich), K₂CO₃ (1.38 g, Aldrich) and DMF (30 ml,Aldrich) at 40° C. for 48 h. The DMF was removed in vacuo and theresidue was diluted with EtOAc (80 ml). The organic phase was washedwith H₂O (50 ml), aqueous Na₂SO₃ (50 ml) and brine (50 ml). Theresulting solution was dried (MgSO₄) and concentrated to provide thecompound which was used as is.

PreparationLXXVIII-2-Bromo-N-(2-hydroxy-5-nitro-phenyl)-2-methyl-propionamide

[0691] 2-Amino-4-nitro-phenol (3.08 g, Aldrich) was stirred with THF (30ml, Aldrich) in an ice bath. 2-Bromo-2-methyl-propionyl bromide (2.47ml, Aldrich) and Et₃N (2.0 g, Aldrich) was slowly added via syringe. Themixture was stirred for 45 min then poured into ice. The aqueous phasewas extracted by EtOAc (50 mL×4). The organic layer was dried andconcentrated. The desired compound was crystallized from EtOAc. (Chem.Pharm. Bull 1996, 44(1) 103-114).

Preparation LXXIX-2,2-Dimethyl-6-nitro-4H-benzo[1,4]oxazin-3-one

[0692] 2-Bromo-N-(2-hydroxy-5-nitro-phenyl)-2-methyl-propionamide wasmixed with K₂CO₃ in 20 mL of DMF and stirred overnight at 50° C. Thereaction mixture was poured into ice H2O. The precipitate was collectedby filtration and washed with H₂O. The crude compound was recrystallizedfrom EtOH.

PreparationLXXX-4-[1-(2-Bromo-4-nitro-phenyl)-1-methyl-ethyl]-1-methyl-pyridiniumiodide

[0693] 1-Methyl-4-[1-methyl-1-(4-nitro-phenyl)-ethyl]-pyridinium (8 g)was dissolved in glacial HOAc (10 ml) then diluted with H₂SO₄ (50 ml),then NBS (3.8 g) was added. After 1 h, additional NBS (1.2 g) was added,30 min later another 0.5 g of NBS, then 15 min later 200 mg more NBS.After 1 h, the mixture was neutralized with NH₄OH (conc.) with ice bathcooling. The neutralized mixture was then concentrated and used as is.

PreparationLXXXI-4-[1-(2-Bromo-4-nitro-phenyl)-1-methyl-ethyl]-1-methyl-1,2,3,6-tetrahydro-pyridine

[0694]4-[1-(2-Bromo-4-nitro-phenyl)-1-methyl-ethyl]-1-methyl-pyridiniumiodidewas mixed with MeOH (400 ml) and CH₂Cl₂ (200 ml), then treated withNaBH₄ (2.5 g) in portions. After stirring at RT for 2 h, the mixture wasextracted with CH₂Cl₂ (300 mL×3). The CH₂Cl₂ layer was washed withbrine, dried over Na₂SO₄ and concentrated in vacuo, to provide thedesired compound.

PreparationLXXXII-1-Methyl-4-[1-methyl-1-(4-nitro-phenyl)-ethyl]-pyridinium iodide

[0695] 4-(4-Nitro-benzyl)-pyridine (4.3 g) was mixed with MeI (4 ml,9.12 g)/NaOH (5N, 30 ml), Bu₄NI (150 mg) and CH₂Cl₂ (50 ml) and stirredat RT overnight. Additional Mel (2 mL) was added along with 50 mL ofNaOH (5N). 6 h later, more MeI (2 mL) was added. The mixture was stirredat RT over the weekend. The mixture was cooled on ice bath and the basewas neutralized by conc. HCl (aq) addition dropwise to pH 7. Thecompound was used as is.

PreparationLXXXIII-1-Methyl-4-(4-nitro-benzyl)-1,2,3,6-tetrahydro-pyridine

[0696] 4-(4-Nitrobenzyl)pyridine (64 g) and TBAI (6 g) were dissolved inCH₂Cl₂ (500 mL) and the solution was suspended with NaOH (aq. 5N, 450mL) in a 3L 3-necked round bottom flask. With vigorous stirring, CH3I(213 g) was added and stirred vigorously at RT for 60 h (or until bluecolor disappears). The reaction was quenched with dimethylamine (100 mL)and MeOH (300 mL) and stirred for 2 h. NaBH₄ (19 g) was added to themixture in small portions. The reaction mixture was stirred for 30 minat RT, then partitioned between CH₂Cl₂/H₂O (500 mL/500 mL). The organiclayer was collected and the aqueous layer was washed with CH₂Cl₂ (300mL×3). The combined organic layers was washed with brine thenconcentrated in vacuo. The residue was purified on a silica wash-column(7% TEA in EtOAc). The desired fractions were combined and concentratedunder vacuum to give the desired compound as a dark gray solid. (MS:M+1=261).

Preparation LXXXIV -1-Boc-4-formylpiperidine

[0697] 4A Molecular sieves were heated to 100° C. and a vacuum wasapplied. They were cooled to RT and purged with N2. CH₂Cl₂ (420 ml) andCH₃CN (40 ml), NMO (40 g) and 1-Boc-4-hydroxymethylpiperidine (50 g)were added and the mix was stirred for 5 min then cooled to 15° C. TPAP(4.1 g) is added and an exotherm was observed. The reaction wasmaintained at RT with external cooling. The reaction was stirred at RTfor 3 h, filtered, concentrated, diluted with 50% EtOAc/hexanes andpurified on a silica gel plug (50% EtOAc/hexanes). The eluant fractionswere concentrated to afford a yellow oil.

Preparation LXXXV-2-Chloro-4-cyanopyridine

[0698] 2-Chloro-4-cyanopyridine was prepared similar to the methoddescribed by Daves et al., J. Het. Chem., 1, 130-32 (1964).

Preparation LXXXVI-4-(2-tert-Butyl-5-nitro-phenyl)-but-3-en-1-ol

[0699] A mix of 1-(tert-butyl)-2-bromo-4-nitrobenzene (3.652 g), TEA(5.92 ml), 3-buten-1-ol (5.48 ml), Pd(OAc)₂ (32 mg), Pd(PPh₃)₄ (327 mg)and toluene (40 ml) was degassed with nitrogen and heated in a sealedvessel for 16 h at 120° C. The next day, the reaction mixture was cooledto RT, filtered, and concentrated in vacuo. The crude was eluted on asilica gel column with 15% to 22% EtOAc/hexanes gradient system to yielda yellow-brown oil.

Preparation LXXXVII-4-(2-tert-Butyl-5-nitro-phenyl)-but-3-enal

[0700] 4-(2-tert-Butyl-5-nitro-phenyl)-but-3-en-1-ol (1.024 g) wasdissolved in 10 ml of CH₂Cl₂ and added dropwise over 5 min to a −78° C.mix of oxalyl chloride (0.645 ml), DMSO (0.583 ml), and 10 ml CH₂Cl₂.The reaction was stirred at −78° C. for 1 h, then treated with asolution of TEA (1.52 ml) in 7 ml CH₂Cl₂ and stirred at −78° C. for anadditional 25 min, then warmed to −30° C. for 35 min. The reaction wastreated with 50 ml of saturated aqueous NH₄Cl, diluted with H₂O andextracted with EtOAc. The organic layer was brine-washed, dried overNa₂SO₄, filtered, and concentrated in vacuo to yield a yellow oil whichwas used as is in Preparation LXXXVIII.

PreparationLXXXVIII-1-[4-(2-tert-Butyl-5-nitro-phenyl)-but-3-enyl]-pyrrolidine:

[0701] 4-(2-tert-Butyl-5-nitro-phenyl)-but-3-enal (895 mg) was dissolvedin 40 ml THF, and to the solution was added pyrrolidine (0.317 ml). Tothe deep orange solution was added NaBH(OAc)₃ (1.151 g) and glacial AcOH(0.207 ml). The reaction was stirred at RT overnight, then treated withsaturated aqueous NaHCO₃ and diluted with Et₂O and some 1N NaOH. Thelayers were separated, and the organic layer was extracted with aqueous2N HCl. The acidic aqueous layer was basified to pH>12 with 6 N NaOH,extracted with Et₂O, brine-washed, dried over Na₂SO₄, filtered, andconcentrated in vacuo to provide1-[4-(2-tert-butyl-5-nitro-phenyl)-but-3-enyl]-pyrrolidine as aorange-brown oil.

Preparation LXXXIX-N-Boc-(2-chloropyrimidin-4-yl)-methylamine

[0702] To 2-chloropyrimidine-4-carbonitrile [2.5 g, prepared by theprocedure of Daves et. al. [J. Het. Chem. 1964, 1, 130-132)] in EtOH(250 ml) under N₂ was added Boc₂O (7.3 g). After the mixture was brieflyplaced under high vacuum and flushed with N₂, 10% Pd/C (219 mg) wasadded. H₂ was bubbled though the mixture (using balloon pressure with aneedle outlet) as it stirred 4.2 h at RT. After filtration throughCelite®, addition of 1.0 g additional Boc₂O, and concentration, theresidue was purified by silica gel chromatography (5:1→4:1hexanes/EtOAc) to obtain N-Boc-(2-chloropyrimidin-4-yl)-methylamine.

Preparation XC-Methanesulfonic acid 1-Boc-azetidin-3-ylmethyl ester

[0703] To a solution of (1-Boc-azetidin-3-yl)-methanol (1.06 g, 5.7mmol), TEA (1.18 mL, 8.52 mmol) in CH₂Cl₂ at 0° C. was added MeSO₂Cl(0.53 mL, 6.82 mmol) via a syringe. The reaction was warmed to RT over 2h and stirring was continued at RT for 2 h. The white solid formed wasremoved by filtration and the filtrate was washed with 25 mL of H₂O. Theorganic phase was dried over Na₂SO₄, and concentrated in vacuo to affordyellow oil.

Preparation XCI-N-(2-bromo-5-nitrophenyl)acetamide

[0704] 2-Bromo-5-nitroaniline (10 g) was dissolved in 500 mL of CH₂Cl₂,DIEA (6.6 g) was added to the mixture, followed by DMAP (100 mg). Themixture was cooled to 0° C. in ice bath. Acetyl chloride (4 g in 50 mLCH₂Cl₂) was added dropwise to the reaction mixture. After the mixturewas stirred at RT over 3 h, extracted once with saturated NaHCO₃solution and once with brine, the resulting organic layer was dried overMgSO₄, filtered and concentrated in vacuo. The crude material waspurified by flash chromatography on silica gel with 1:1 EtOAc:Hexane to100% EtOAc to afford N-(2-bromo-5-nitrophenyl)acetamide as a whitesolid. MS: 258 (M−1). Calc'd. for C₈H₇BrN₂O₃-259.06.

PreparationXCII-N-(2-bromo-5-nitrophenyl)-N-(2-methylprop-2-enyl)acetamide

[0705] A suspension of 2 g NaH (95% powder) in anhydrous DMF (100 mL)was cooled to −78° C., N-(2-bromo-5-nitrophenyl)acetamide (7 g) in dryDMF (50 mL) was added to the mixture under N₂ atmosphere. After themixture was warmed to 0° C., 3-bromo-2-methylpropene (7.3 g in 20 dryDMF) was added to the mixture. The mixture was stirred at RT overnight.The mixture was poured into a container of ice and extracted betweensaturated NaHCO₃ solution and EtOAc. The resulting organic layer wasdried over MgSO₄, filtered and concentrated in vacuo. The crude materialwas purified by flash chromatography on silica gel with 7:2 hexane:EtOActo afford the title compound as a yellow gum. MS: 314 (M+1). Calc'd. forC₁₂H₁₃BrN₂O₃-313.15.

PreparationXCIII-1-(3,3-dimethyl-6-nitro-2,3-dihydro-indol-1-yl)ethanone

[0706] N-(2-Bromo-5-nitrophenyl)-N-(2-methylprop-2-enyl)acetamide (4.5g) was dissolved in anhydrous DMF (50 mL), tetraethyl-ammonium chloride(2.5 g), sodium formate (1.2 g), NaOAc (3 g) were added, and theresulting mixture was bubbled with N₂ gas for 10 min. Pd(OAc)₂ (350 mg)was added and the mixture was heated at 80° C. under N₂ atmosphereovernight. After the mixture was concentrated in vacuo, it waspartitioned between saturated NaHCO₃ solution and EtOAc, the resultingorganic layer was dried over MgSO₄, filtered and concentrated in vacuo.The crude material was purified by flash chromatography on silica gelwith 2:1 Hexane:EtOAc to afford the title compound as a yellow gum. MS:235 (M+1). Calc'd. for C₁₂H₁₄N₂O₃-234.25.

Preparation XCIV-3,3-dimethyl-6-nitroindoline

[0707] 1-(3,3-Dimethyl-6-nitro-2,3-dihydro-indol-1-yl)ethanone (1.8 g)was dissolved in EtOH (50 mL), 12N HCl (50 mL) was added and theresulting mixture was heated at 70° C. overnight. After the mixture wasconcentrated in vacuo, it was partitioned between saturated NaHCO₃solution and EtOAc, the resulting organic layer was dried over MgSO₄,filtered and concentrated in vacuo to afford a yellow solid. MS: 193(M+1). Calc'd. for C₁₀H₁₂N₂O₂-192.21.

Preparation XCV-1-Acetyl-6-amino-3,3-dimethylindoline

[0708] 1-(3,3-Dimethyl-6-nitro-2,3-dihydro-indol-1-yl)ethanone (250 mg)was dissolved in MeOH (20 mL), the mixture was bubbled with H₂ for 10min. 10% Pd/C (50 mg) was added and the mixture was stirred under H₂overnight. The mixture was filtered through Celite® and concentrated invacuo. The crude material was purified by flash chromatography on silicagel with 1:1 EtOAc:CH₂Cl₂ to afford the title compound as a whitecrystalline material. MS: 205 (M+1). Calc'd. for C₁₂H₁₆N₂O-204.27.

Preparation XCVI-4-(1,1,2,2,3,3,4,4,4-nonafluorobutyl)phenylamine

[0709] 4-Nitro-(1,1,2,2,3,3,4,4,4-nonafluorobutyl)benzene wassynthesized by a method analogous to that described by Gregory, W. A. etal. (J. Med. Chem, 1990, 33(9) 2569-2578). The mixture of the abovenitro intermediate (1.0 mmol), iron powder (5.0 mmol) and NH₄Cl (0.7mmol) in EtOH (3 mL) and H₂O (3 ml) was stirred for 4 h at 80° C.Filtration and concentration gave the crude title compound, which wasused without further purification.

Preparation XCVII-2-bromo-1-tert-butyl-4-nitrobenzene

[0710] NBS (125.0 g, 697.5 mmol, 1.5 eq) was slowly added to a solutionof TFA:H₂SO₄ (5:1, 750 mL) and tert-butyl-4-nitrobenzene (100.0 g, 558.0mmol) at RT. The solution was stirred for 24 h and poured over 5 kg ofice. The resulting suspension was filtered and washed with a 1:1MeOH:H₂O solution (200 mL) and dried in a vacuum oven. MS (ES+): 258.1,260.1 (M+H)⁺. Calc'd for C₁₀H₁₂BrNO₂: 257.0.

Preparation XCVIII-4-(2-tert-butyl-5-nitrophenyl)pyridine

[0711] To a solution of 2-bromo-1-tert-butyl-4-nitrobenzene (8.6 g, 33.3mmol) and toluene (70 mL) in a 150 mL round bottom flask,4-pyridylboronic acid (4.5 g, 36.6 mmol, 1.1 eq), Pd(PPh₃)₄ (3.8 g, 3.3mmol, 0.1 eq) and K₂CO₃ (13.8 g, 99.9 mmol, 3 eq) were added. Thesolution was stirred for 24 h at 80° C. before cooling to RT. Thesolution was filtered through a pad of Celite® and purified by silicaflash chromatography (30% EtOAc/Hexanes). This afforded the desiredcompound as a yellow solid. MS (ES+): 257.2 (M+H)⁺; (ES−): 255.2 (M−H)⁻.Calc'd for C₁₅H₁₆N₂O₂: 256.1.

Preparation XCIX-4-(2-tert-butyl-5-nitrophenyl)-1-methylpyridinium

[0712] 4-(2-tert-Butyl-5-nitrophenyl)pyridine (2.0 g, 7.8 mmol) wasadded to a round-bottom flask and dissolved in EtOH (10 mL). CH₃I (30mL) was added to the flask which was placed in a 80° C. sand bath andheated to reflux. After 6 h, the solution was cooled to RT and theexcess CH₃I and EtOH were stripped-off under reduced pressure resultingin the desired compound as a light brown solid. MS (ES+): 271.2 (M+H)⁺;(ES−): 269.2 (M−H)⁻. Calc'd for C₁₆H₁₉N₂O₂ ⁺: 271.1.

PreparationC-4-tert-butyl-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)aniline

[0713] 4-(2-tert-Butyl-5-nitrophenyl)-1-methylpyridinium (2.1 g, 7.8mmol, Step C) was added to a 100 mL round-bottom flask and dissolved ina 10% H₂O/EtOH mixture. To the flask iron dust (1.31 g, 23.4 mmol, 3 eq)and NH₄Cl (460 mg, 8.6 mmol, 1.1 eq) were added. The flask was placed ina 100° C. sand bath and heated to reflux. After 2 h, the solution wascooled to RT and filtered through a pad of Celite®. The resultingsolution was stripped down to a yellow solid and redissolved in MeOH (20mL, anhydrous). The solution was cooled to 0° C. by placing it in an icebath and slowly adding NaBH₄ (450 mg, 11.7 mmol, 1.5 eq). After additionof the NaBH₄, the solution was cooled to RT and stirred for 30 min. Thesolvent was stripped-off under vacuum and the solid was redissolved inCH₂Cl₂ and filtered. The solution was concentrated in vacuo to afford anamorphous clear yellow solid. MS (ES+): 245.2 (M+H)⁺. Calc'd forC₁₆H₂₄N₂: 244.2.

Preparation CI-[1-(4-amino-phenyl)-ethyl]carbamic acid tert-butyl ester

[0714] A mixture of 1-(S)-1-(4-nitrophenyl)ethylamine hydrochloride (2g), Boc₂O (2.6 g) and NaHCO₃ (3 g) in MeOH/H₂O (1:1, 200 ml) was stirredat RT overnight. The reaction was extracted with EtOAc twice then washedwith H2O followed by brine. The organic layer was dried with Na₂SO₄ andevaporated under reduced pressure to give the protected nitrophenylethylamine. Boc-1-(S)-1-(4 nitrophenyl)ethylamine (1 g) was hydrogenatedby H₂ atmosphere in the presence of Pd/C (200 mg) to give Boc protectedaniline (0.8 g). The intermediate was deprotected with 4N HCl/dioxane togive the title compound as the HCl salt.

Preparation CII-1-[2-(tert-butyl)-5-aminophenyl]-4-methylpiperazine

[0715] A mixture of 2-t-butylaniline (5.4 g) and methylchlorethylaminehydrochloride (7 g) and K₂CO₃ (5 g) in NaI (2 g) in diglyme (150 m) washeated at 170° C. for 8 h. The reaction was filtered and the filtratewas evaporated under high vacuum. The residue was mixed with EtOAc (200ml) and H₂O (200 ml) and extracted with EtOAc twice. The combinedorganic layer was washed with brine and dried over Na₂SO₄ and evaporatedto give crude 1-[2-(tert-butylphenyl]-4-methylpiperazine. The crude1-[2-(tert-butylphenyl]-4-methylpiperazine (260 mg) was stirred withH₂SO₄ (3 ml) at 0° C. and HNO₃ (1.2 ml, 70%) was slowly added to thereaction. The reaction was warmed to RT, stirred for 30 min, poured onice and basified with K₂CO₃ slowly. The solution was extracted withEtOAc three times, washed with H₂O, followed by brine, dried over Na₂SO₄and evaporated under reduced pressure. The residue was purified bycolumn chromatography to give1-[2-(tert-butyl)-5-nitrophenyl]-4-methylpiperazine (260 mg), which washydrogenated under H₂ atmosphere to give1-[2-(tert-butyl)-5-aminophenyl]-4-methylpiperazine.

[0716] The following compounds were prepared similarly to the procedureoutlined above:

[0717] a) 1-(5-aminophenyl)-4-methylpiperazine

Preparation CIII-4-(tert-butyl)-2-(4-methylpiperazinyl)phenylamine

[0718] A mixture of 1-(tert-butyl)-2-bromo-4-nitrobenzene (3 g) andN-methylpiperazine (8 g) was heated neat at 130° C. for 4 h. The residuewas purified by column chromatography to give1-(4-bromo-5-(tert-butyl)-2-nitrophenyl]-4-methylpiperazine, which washydrogenated to furnish4-(tert-butyl)-2-(4-methylpiperazinyl)-phenylamine.

Preparation CIV-{2-[4-(tert-butyl)-2-aminophenoxy]ethyl}dimethylamine

[0719] DEAD (2.6 ml)was added to a mixture of 2-nitro-4-tert-butylphenol(2 g) and N,N-dimethylethanolamine (1.3 g) and Ph₃P (4 g) in THF (50ml). The reaction was stirred at RT for 1 h, diluted with EtOAc (50 ml)and washed with 1 N HCl twice. The aqueous layer was basified withNaHCO₃, extracted with EtOAc twice and washed with H₂O and brine. Theorganic layer was dried over Na₂SO₄ and evaporated to give{2-[4-(tert-butyl)-2-nitrophenoxy]ethyl}-dimethylamine. It washydrogenated under H₂ atmosphere to give{2-[4-(tert-butyl)-2-aminophenoxy]ethyl}-dimethylamine.

[0720] The following compounds were prepared similarly to the procedureoutlined above:

[0721] a) [2-(2-aminophenoxy)ethyl]-dimethylamine.

Preparation CV-2-amino-5,6,7-trihydro-1,2,4-triazolo[3,4-a]isoquinoline

[0722] 7-Nitro-2,3,4-trihydroisoquinolin-1-one (500 mg) was heated inPOCl₃ (10 ml) to reflux for 8 h. The mixture was evaporated, mixed withtoluene and evaporated again. The residue was dissolved in THF, H₂NNH₂(1 ml) was slowly added to the reaction and stirred for 2 h. Thereaction was evaporated, heated with HC(OEt)₃ (15 ml) at 115° C. for 2h, extracted with EtOAc and hydrogenated to give2-amino-5,6,7-trihydro-1,2,4-triazolo[3,4-a]isoquinoline.

Preparation CVI-tert-butyl4-[(6-nitro-3,3-dimethylindolinyl)methyl]piperidinecarboxylate

[0723] 3,3-Dimethyl-6-nitroindoline (450 mg) was dissolved in 20 mL ofdichloroethane, N-boc-4-formylpiperidine (750 mg) was added to themixture, followed by 2 g NaHB(OAc)₃ and 1 mL of glacial AcOH. Themixture was stirred at RT overnight. Saturated NaHCO₃ solution (20 mL)was added to the reaction mixture and stirred for 1 h. The resultingmixture was separated by separation funnel, the organic layer wasextracted once with saturated NaHCO₃ solution and once with brine. Theresulting organic layer was dried over MgSO₄, filtered and concentratedin vacuo. The crude material was purified by flash chromatography onsilica gel with 9:1 Hexane:EtOAc to afford an orange oil. MS: 290(M−99). Calc'd. for C₂₁H₃₁N₃O₄-389.5.

PreparationCVII-3,3-dimethyl-1-piperidin-4-ylmethyl-2,3-dihydro-1H-indol-6-ylamine

[0724] tert-Butyl4-[(6-nitro-3,3-dimethylindolinyl)-methyl]piperidinecarboxylate (900 mg)was dissolved in 10 mL MeOH, the mixture was bubbled with H₂ for 10 min.10% Pd/C (30 mg) was added and the mixture was stirred under H₂overnight. The mixture was filtered through Celite® and concentrated invacuo. The crude material was purified by flash chromatography on silicagel with 1:1 Hexane:EtOAc to afford a colorless oil. MS: 360 (M+1).Calc'd. for C₂₁H₃₃N₃O₂-359.5.

Preparation CVIII-(2-chloro-(3-pyridyl))-N-(4-phenoxyphenyl)carboxamide

[0725] 2-Chloronicotinoyl chloride (9.15 g, 0.052 mol) was added to astirred solution of 4-phenoxyaniline (10 g, 0.054 mol) and DIEA (10 ml,0.057 mol) in CH₂Cl₂ (100 ml) at RT. The mixture was stirred for 48 hbefore removal of solvent under reduced pressure. The resulting residuewas dissolved in EtOAc and washed several times with saturated NaHCO₃aqueous solution and brine, respectively. The organic layer was driedover Na₂SO₄ and evaporated to leave a solid. This material wasre-crystallized from EtOAc/Hexane mixture, followed by filtration andrinsing with Et₂O to give the desired compound as a white solid. MS m/z:325 (M+1); 323 (M−1).

Preparation CIX-1-(1-methyl(4-piperidyl))-6-nitroindoline

[0726] 6-Nitroindoline (5 g) was dissolved in 200 mL of dichloroethane.N-Methyl-4-piperidone (5 g) was added to the mixture, followed byNaHB(OAc)₃ (12 g) and 1 mL of glacial AcOH. The mixture was stirred atRT overnight. A saturated NaHCO₃ (200 mL) solution was added to thereaction mixture and stirred for 1 h. The resulting mixture wasseparated by separation funnel. The organic layer was extracted oncewith saturated NaHCO₃ solution and once with brine. The resultingorganic layer was dried over MgSO₄, filtered and concentrated in vacuo.The crude material was purified by flash chromatography on silica gelwith 2:1 EtOAc:MeOH to afford orange oil. MS: 262 (M+1). Calc'd. forC₁₄H₁₉N₃O₂-261.3.

Preparation CX-1-(1-methyl-4-piperidyl)indoline-6-ylamine

[0727] 1-(1-Methyl(4-piperidyl))-6-nitroindoline (3 g) was dissolved in100 mL MeOH and the mixture was bubbled with H₂ for 10 min. 10% Pd/C(200 mg) was added and the mixture was stirred under H₂ overnight. Themixture was filtered through Celite® and concentrated in vacuo to affordlight yellow oil. MS: 232 (M+1). Calc'd. for C₁₄H₂₁N₃-231.3.

Preparation CXI-N-(2-bromo-5-nitrophenyl)acetamide

[0728] 2-Bromo-5-nitroaniline (10 g) was dissolved in CH₂Cl₂ (500 mL),DIEA (6.6 g) was added to the mixture, followed by 100 mg of DMAP. Themixture was cooled to 0° C. in ice bath. Acetyl chloride (4 g in 50 mLCH₂Cl₂) was added dropwise to the reaction mixture. After the mixturewas stirred at RT over 3 h, and extracted once with saturated NaHCO₃solution and once with brine. The resulting organic layer was dried overMgSO₄, filtered and concentrated in vacuo. The crude material waspurified by flash chromatography on silica gel with 1:1 EtOAc:Hexane to100% EtOAc to afford a white solid. MS: 258 (M−1). Calc'd. forC₈H₇BrN₂O₃-259.1.

PreparationCXII-N-(2-bromo-5-nitrophenyl)-N-(2-methylprop-2-enyl)acetamide

[0729] A suspension of NaH (2 g) (95% powder) in 100 mL anhydrous DMFwas cooled to −78° C., and N-(2-bromo-5-nitrophenyl)acetamide (7 g) in50 mL dry DMF was added to the mixture under N₂. After the mixture waswarmed to 0° C., 3-bromo-2-methylpropene (7.3 g in 20 dry DMF) was addedto the mixture. The mixture was stirred at RT overnight. The mixture waspoured into a container of ice and extracted between saturated NaHCO₃solution and EtOAc. The resulting organic layer was dried over MgSO₄,filtered and concentrated in vacuo. The crude material was purified byflash chromatography on silica gel with 7:2 Hexane:EtOAc to afford ayellow gum. MS: 314 (M+1). Calc'd. for C₁₂H₁₃BrN₂O₃-313.1.

PreparationCXIII-1-(3,3-dimethyl-6-nitro-2,3-dihydro-indol-1-yl)ethanone

[0730] N-(2-Bromo-5-nitrophenyl)-N-(2-methylprop-2-enyl)acetamide (4.5g) was dissolved in 50 mL anhydrous DMF, 2.5 g tetraethyl-ammoniumchloride, 1.2 g sodium formate, 3 g sodium acetate were added, theresulting mixture was bubbled with N₂ gas for 10 min. Pd(OAc)₂ (350 mg)was added and the mixture was heated at 80° C. under N₂ overnight. Afterthe mixture was concentrated in vacuo, it was extracted betweensaturated NaHCO₃ solution and EtOAc, the resulting organic layer wasdried over MgSO₄, filtered and concentrated in vacuo. The crude materialwas purified by flash chromatography on silica gel with 2:1 Hexane:EtOActo afford a yellow gum. MS: 235 (M+1). Calc'd. for C₁₂H₁₄N₂O₃-234.2.

Preparation CXIV-3,3-dimethyl-6-nitroindoline

[0731] 1-(3,3-Dimethyl-6-nitro-2,3-dihydro-indol-1-yl)ethanone (1.8 g)was dissolved in 50 mL EtOH, 50 mL 12N HCl was added and the resultingmixture was heated at 70° C. overnight. After the mixture wasconcentrated in vacuo, it was extracted between saturated NaHCO₃solution and EtOAc. The resulting organic layer was dried over MgSO₄,filtered and concentrated in vacuo to afford a yellow solid. MS: 193(M+1). Calc'd. for C₁₀H₁₂N₂O₂-192.2.

PreparationCXV-3,3-dimethyl-1-(4-methyl-piperazin-1-yl)-6-nitro-2,3-dihydro-1H-indole

[0732] 3,3-Dimethyl-6-nitroindoline (0.8 g) was dissolved in 50 mL ofdichloroethane, N-methyl-4-piperidone (1 g) was added to the mixture,followed by 2.5 g NaHB(OAc)₃ and 1 mL of glacial AcOH. The mixture wasstirred at RT overnight. Saturated NaHCO₃ solution (50 mL) was added tothe mixture and stirred for 1 h. The resulting mixture was separated byseparation funnel, the organic layer was extracted once with saturatedNaHCO₃ solution and once with brine, the resulting organic layer wasdried over MgSO₄, filtered and concentrated in vacuo. The crude materialwas purified by flash chromatography on silica gel with 9:1 EtOAc:MeOHto afford an orange oil. MS: 290 (M+1). Calc'd. for C₁₆H₂₃N₃O₂-289.4.

PreparationCXVI-3,3-dimethyl-1-(1-methyl(4-piperidyl))indoline-6-ylamine

[0733]3,3-Dimethyl-1-(4-methyl-piperazin-1-yl)-6-nitro-2,3-dihydro-1H-indole(600 mg) was dissolved in 20 mL MeOH, the mixture was bubbled with H₂for 10 min. 10% Pd/C (100 mg) was added and the mixture was stirredunder H₂. The mixture was filtered through Celitee and concentrated invacuo to afford an oil. MS: 260 (M+1). Calc'd. for C₁₆H₂₅N₃-259.4.

PreparationCXVII-3-(1-methyl-1,2,3,6-tetrahydro-pyridin-4-yl)-5-nitro-1H-indole

[0734] 5-Nitroindole (2.6 g) was dissolved in 100 mL anhydrous MeOH,followed by 5 g N-methyl-4-piperidone and NaOMe (5 g) powder. Themixture was heated to reflux under N₂ overnight. The mixture wasconcentrated in vacuo, and was extracted between saturated NaHCO₃solution and EtOAc. The resulting organic layer was dried over MgSO₄,filtered and concentrated in vacuo to afford a yellow solid. This solidwas washed with 5 mL EtOAc and 2 mL MeOH to afford a bright yellowsolid. MS: 258 (M+1). Calc'd. for C₁₄H₁₅N₃O₂-257.29.

Preparation CXVIII-3-(1-methyl-4-piperidyl)indole-5-ylamine

[0735] 3-(1-Methyl-1,2,3,6-tetrahydro-pyridin-4-yl)-5-nitro-1H-indole(2.7 g) was dissolved in 50 mL MeOH, the mixture was bubbled with H₂ for10 min. 10% Pd/C (150 mg) was added and the mixture and stirred under H₂overnight. The mixture was filtered through Celite® and concentrated invacuo to afford a yellow oil. MS: 230 (M+1). Calc'd. for C₁₄H₁₉N₃-229.3.

PreparationCXIX-{3-[3-amino-5-(trifluoromethyl)phenyl]propynyl}dimethylamine

[0736] A mixture of 3-bromo-5-trifluoromethylaniline (1.4 g, 5.9 mmol),1-dimethylamino-2-propyne (1.3 mL, 0.76 mmol), PdCl₂(PPh₃)₂ (0.26 g,0.29 mmol) and CuI (114 mg, 0.60 mmol) in 10 mL of TEA was heated at100° C. in a sealed tube for 3 h. The resulting mixture was filteredover Celite®. The filtrate was concentrated, and the residue waspurified by prep-HPLC (reverse phase) to give the aniline. MS (ES+): 243(M+H)⁺; (ES−): 241 (M−H)⁻. Calc'd C₁₂H₁₃F₃N₂-242.24.

PreparationCXX-{3-[3-amino-5-(trifluoromethyl)phenyl]propyl}dimethylamine

[0737] A mixture of{3-[3-amino-5-(trifluoromethyl)-phenyl]propyl}dimethylamine (7 g, 29mmol) and Pd(OH)₂ (0.5 g)in 250 mL of MeOH was stirred under 50 psi H₂.After 2 h, the resulting mixture was filtered over Celite®. The filtratewas concentrated, and the residue was diluted with aq. 1N HCl. The aq.layer was washed with Et₂O, made basic with aq. 5N NaOH, and extractedwith CH₂Cl₂. The organic solution was dried over Na₂SO₄ and concentratedto give the titled compound. MS (ES+): 386 (M+H)⁺; (ES−): 384 (M−H)⁻.Calc'd C₁₈H₁₉ClF₃N₃O-385.8.

PreparationCXXI-4,4,5,5-tetramethyl-2-(1-methyl(4-1,2,5,6-tetrahydropyridyl))-1,3,2-dioxaborolane

[0738] To a solution of LiHMDS (25 mL, 25 mmol, 1.0 M in THF) in 35 mLof THF was added 1-methyl-4-piperidinone (3.0 mL, 25 mmol) at −78° C.The resulting solution was stirred for 2 h, then Tf₂NPh (8.9 g, 25 mmol)was added. The resulting solution was warmed to RT and stirred for 2 h.The mixture was concentrated, and the residue was purified by alumina(neutral) chromatography to give1-methyl-4-(1,2,5,6-tetrahydro)pyridyl-(trifluoromethyl) sulfonate. Amixture of above triflate (5.0 g, 20 mmol), bis(pinacolato)diboron (5.6g, 22 mmol), potassium acetate (6.5 g, 66 mmol), PdCl₂dppf (0.44 g, 0.6mmol), and (dppf)2 (0.33 g, 0.6 mmol) in 60 mL of dioxane was heated at80° C. for 4 h. The resulting mixture was cooled to RT, diluted withEt₂O (150 mL). The ethereal solution was washed with H₂O followed bybrine. The organic layer dried over Na₂SO₄, concentrated, andrecrystallized in hexane-Et₂O to give the title intermediate.

PreparationCXXII-5-(1-methyl(4-1,2,5,6-tetrahydropyridyl))-3-(trifluoro-methyl)phenylamine

[0739] To a mixture of4,4,5,5-tetramethyl-2-(1-methyl(4-1,2,5,6-tetrahydropyridyl))-1,3,2-dioxaborolane(1.0 g, 4.4 mmol), PdCl₂pddf (0.16 g, 0.2 mmol) and K₂CO₃ (1.8 g, 13.2mmol) and 3-amino-5-bromobenzotrifluoride (0.8 g, 3.3 mmol) in DMF (25mL) was heated at 80° C. for 16 h. The resulting mixture was dilutedwith EtOAc, washed with H₂O, dried over Na₂SO₄, and concentrated. Theresidue was purified by SiO₂ chromatography to give the titleintermediate. MS (ES+): 257 (M+H)⁺. Calc'd C₁₃H₁₅F₃N₂-256.3.

Preparation CXXIII-4-phenylpiperidine

[0740] 4-Cyano-4-phenylpiperidine HCl (10.0 g, 45.0 mmol) was combinedwith KOH pellets and stirred vigorously under Ar at 160° C. for 4 h. Thereaction mix was cooled to RT and dissolved into toluene (100 ml) andH₂O (100 ml). After separation of the layers, the aqueous layer wasback-extracted two times with toluene. The combined organic layer wasdried over Na₂SO₄, concentrated in vacuo, and dried under high vacuum,yielding a white solid.

Preparation CXXIV-1-methyl-4-phenylpiperidine

[0741] To a stirring mixture at RT of 4-phenylpiperidine (5.24 g, 32.48mmol) in CH₃CN (95 ml) was added a 37% solution of HCHO in H₂O (13 ml).To this mixture was added NaCNBH₃ (3.27 g, 51.97 mmol). AcOH was addeddropwise every 10 min over the next h to maintain the reaction pH near7. The reaction volume was then reduced in vacuo. The reaction mix wasdiluted with CH₂Cl₂ and washed with 2N NaOH and then brine. The crudewas concentrated in vacuo and eluted through a silica gel column with10% MeOH/CH₂Cl₂. The 1-methyl-4-phenylpiperidine was concentrated invacuo, yielding a clear oil.

Preparation CXXV-4-(1-methyl-4-piperidyl)phenylamine

[0742] To 1-methyl-4-phenylpiperidine (2.663 g, 15.19 mmol) was addedcarefully H₂SO₄ (15.2 ml). The reaction was cooled in an ice bath and asolution of H₂SO₄ (1.66 ml) and fuming HNO₃ (0.67 ml, 15.95 mmol) wasadded dropwise over 45 min. The mix was stirred at 0° C. for 3 h then atRT for 1.5 h before being poured over about 90 g ice and basified with24 g solid NaOH. The mix was extracted with CH₂Cl₂. The organic layerwas washed with H₂O, dried over Na₂SO₄, and concentrated in vacuo. Thecrude was eluted on a silica gel column with a MeOH/CH₂Cl₂ gradient toyield 1-methyl-4-(4-nitrophenyl)piperidine which was hydrogenated underH₂ to furnish the title compound.

Preparation CXXVI-1-piperidylprop-2-en-1-one

[0743] To a 0° C. solution of acryloyl chloride (4.576 g, 50.558 mmol)in CH₂Cl₂ (50 ml) was added dropwise and very carefully piperidine(4.305 g, 50.558 mmol). The reaction flask was vented during theexothermic addition. After the addition was completed, the white slurrywas stirred at 0° C. for 40 min and at RT for 1 h. The reaction wasdiluted with 70 ml CH₂Cl₂ and washed first with about 60 ml 2N HCl andthen with about 60 ml of a mix of 2N NaOH and brine. The organic layerwas dried over Na₂SO₄. The solution was evaporated by heating in a H₂Obath at 60° C. without vacuum. Once most solvent had been evaporatedoff, dried the clear oil under high vacuum at RT for 30 min.

Preparation CXXVII-1-(tert-butyl)-2-bromo-4-nitrobenzene

[0744] Bromine (17.4 ml) was added dropwise over 40 min to a stirredmixture of 4-tert-butylnitrobenzene (59.5 g, 332 mmol),silver(II)sulfate (56.5 g, 181 mmol), H₂SO₄ (300 ml), and H₂O (33 ml) atRT. The mixture was stirred for a further 3 h and then poured into 0.1 MNa₂S₂O₅/H₂O (1L). The solid was filtered, washed with H₂O, Et₂O, andCH₂Cl₂. The filtrate layers were separated. The aqueous fraction wasextracted with Et₂O. The combined organic layers were combined, driedover Na₂SO₄, and concentrated in vacuo. The yellow solid was trituratedwith hexanes to give a pale yellow crystalline solid.

PreparationCXXVIII-(2E)-3-[2-(tert-butyl)-5-nitrophenyl]-1-piperidylprop-2-en-1-one

[0745] 1-(tert-Butyl)-2-bromo-4-nitrobenzene (6.885 g, 26.674 mmol),1-piperidylprop-2-en-1-one (4.827 g, 34.677 mmol), and TEA (7.44 ml,53.35 mmol) were dissolved in toluene (70 ml). To this solution wasadded Pd(OAc)₂ (60 mg, 0.267 mmol) and Pd(PPh₃)₄ (617 mg, 0.5335 mmol).The mix was degassed with N₂ and heated in a sealed vessel at 120° C.for 15 h. The reaction mixture was cooled to RT, filtered, andconcentrated in vacuo. The dark crude oil was eluted through a silicagel column with 15% to 22% EtOAc/hexanes gradient system to yield athick amber oil as the title compound.

PreparationCXXIX-3-(5-amino-2-tert-butylphenyl)-1-piperidin-1-yl-propenone

[0746] (2E)-3-[2-(tert-Butyl)-5-nitrophenyl]-1-piperidylprop-2-en-1-one(3.22 g, 10.177 mmol) was dissolved in dioxane (20 ml) and IpOH (40 ml).To the N₂-degassed solution was added Pd/C 10% by weight catalyst (2 g).The mix was placed in a Parr hydrogenator and stirred for 18 h under 60psi H₂. The reaction was not complete the next day, so the reaction wascontinued for an additional 20 h with fresh catalyst. The mix wasfiltered through Celite® and concentrated in vacuo to give a foamy oil.

Preparation CXXX-4-(tert-butyl)-3-(3-piperidylpropyl)phenylamine

[0747] 3-(5-Amino-2-tert-butylphenyl)-1-piperidin-1-yl-propenone (2.312g, 7.619 mmol) was dissolved in THF (100 ml) at RT. To this solution wasadded LiAlH₄ (434 mg, 11.43 mmol). After the reaction stoppedexotherming, it was heated at reflux at about 80° C. for 4 h. Thereaction mix was cooled to 0° C. and treated by dropwise addition of0.458 ml H₂O, 0.730 ml 10% aqueous NaOH, and 1.19 ml H₂O, respectively.The mix was stirred at RT for 1 h. After 40 min about 3 g of Na₂SO₄ wasadded. The mix was filtered through Celite® and concentrated in vacuo.The crude was eluted through silica gel column with a gradient system of95:5 to 90:10 CH₂Cl₂/MeOH, to yield an amber thick oil as the titlecompound.

[0748] The following compounds were prepared similarly to the procedureoutlined above:

[0749] a) 3-((1E)-4-Pyrrolidinylbut-1-enyl)-4-(tert-butyl)phenylamine.

[0750] b) 4-(tert-Butyl)-3-(3-pyrrolidinylpropyl)phenylamine.

[0751] c) 4-(tert-Butyl)-3-(3-morpholin-4-ylpropyl)phenylamine.

[0752] d) 3-[3-(4-methylpiperazinyl)propyl]phenylamine.

[0753] e) 4-[3-(4-methylpiperazinyl)propyl]phenylamine.

Preparation CXXXI-3-(3-nitrophenyl)-1-(4-methylpiperazinyl)propan-1-one

[0754] A slurry consisting of CH₂Cl₂ (15 ml), 3-nitrocinnamic acid(3.154 g, 16.329 mmol), 1-methylpiperazine (1.487 g, 14.845 mmol) andEDC (3.557 g, 18.556 mmol) were stirred at RT for 60 h. The reaction wasdiluted with H₂O and EtOAc. The aqueous layer was back-extracted withEtOAc. The combined organic layers were washed with 2N NaOH and thenbrine, dried over Na₂SO₄, and concentrated in vacuo. The crude waseluted through a silica gel column with 5% MeOH/CH₂Cl₂, to yield anoff-white solid, mostly trans-olefin compound.

Preparation CXXXII-3-(3-aminophenyl)-1-(4-methylpiperazinyl)propan-1-one

[0755] To a nitrogen-degassed solution of3-(3-nitrophenyl)-1-(4-methylpiperazinyl)propan-1-one (3.67 g, 13.330mmol, Step A) in MeOH (50 ml) was added 10% by weight Pd/C (500 mg). Themix was stirred under H₂ atmosphere for 18 h then filtered throughCelite® and concentrated in vacuo, yielding a thick amber oil whicheventually solidified into a dark pink solid.

[0756] The following compounds were prepared similarly to the procedureoutlined above:

[0757] a) 4-[3-(4-methylpiperazinyl)-3-oxopropyl]phenylamine.

Preparation CXXXIII-1-(2-morpholin-4-ylethyl)indol-6-ylamine

[0758] K₂CO₃ (5.08 g, 36.726 mmol) was added to a slurry of6-nitroindole (1.985 g, 12.242 mmol), 4-(2-chloroethyl) morpholine HCl(2.278 g, 12.242 mmol), and CH₃CN (100 ml). The mix was heated to refluxfor 18 h, then cooled to RT, filtered, and concentrated in vacuo. Thecrude was eluted through a silica gel column with a gradient of 3:97 to5:95 and finally 8:92 MeOH/CH₂Cl₂, to yield upon drying the desiredintermediate which was hydrogenated under conditions previouslydescribed.

Preparation CXXXIV-methyl 2-methyl-2-(4-nitrophenyl)propanoate

[0759] To a stirred solution of 2-(4-nitrophenyl)propionic acid (9 g, 46mmol, 1 eq) in MeOH (300 mL) was added HCl (4M in Dioxane, 11.5 mL, 46mmol, 1 eq). The mixture was stirred at RT overnight and was quenchedwith aqueous NaHCO₃. The mixture was extracted with EtOAc. The organiclayer was dried over MgSO₄ and evaporated under reduced pressure and thepartial residue (4.34 g, 20.7 mmol, leq) at 0° C. in THF (100 mL) wasadded NaH (1.66 g, 41.5 mmol, 2 eq). Mixture was stirred at RT for 1 hand CH₃I (2.58 g, 41.5 mmol, 2 eq) was added. Reaction was stirred at RTovernight and was quenched with H₂O. Mixture was extracted with EtOAc.The organic layer was dried over MgSO₄ and evaporated under reducedpressure and used for the next step without further purification to givetitle compound.

Preparation CXXXV-3-methyl-3-(4-nitrophenyl)butan-1-one

[0760] To a stirred solution of methyl2-methyl-2-(4-nitrophenyl)propionate (5.32 g, 23.8 mmol) in THF (200 mL)at 0° C. was added a solution of 1M BH₃ in THF (25.8 mL, 45.8 mmol). Thereaction was stirred at RT overnight and was quenched with MeOH. THF wasevaporated under reduced pressure and the residue was diluted in EtOAcand aqueous HCl (1M) was added. The mixture was extracted with EtOAc,the organic layer was dried over MgSO₄ and evaporated under reducedpressure. Purification by flash chromatography using 40% EtOAc-hexanegave a yellow solid. To the yellow solid (2.08 g, 10.8 mmol) at 0° C. inCH₂Cl₂ was added NMO (1.9 g, 16.1 mmol), molecular sieves 4A and TPAP(76 mg, 0.2 mmol). The reaction was stirred for 1 h and filtered on asilica pad. Solvent was evaporated under reduced pressure, forming thecrude aldehyde which was used as is. To a suspension ofmethoxymethyltriphenylphosphonium chloride (6.4 g, 18.6 mmol) in THF(150 mL) was added a solution of KHMDS 0.5 M in toluene (37 mL, 18.5mmol). The mixture was stirred for 30 min and crude aldehyde was added.The reaction was stirred at RT for 1 h and quenched with H₂O. Themixture was extracted with EtOAc, dried and evaporated under reducedpressure. Et₂O was added and a precipitate formed, which was filtered ona silica pad and rinsed with 40% EtOAc-hexane. The solvent was removedand crude material was dissolved in CH₂Cl₂. A solution of TFA-H₂O (1:1,10 mL) was added and the reaction was stirred for 2 h at RT. AqueousNaHCO₃ was added until pH 7 and the mixture was extracted with CH₂Cl₂.The organic layer was dried, filtered and evaporated. Crude compound waspurified by flash chromatography (40% EtOAc-hexane) to give the titlecompound as a yellow oil.

Preparation CXXXVI-4-(1,1-dimethyl-3-morpholin-4-ylpropyl)phenylamine

[0761] To a stirred solution of 3-methyl-3-(4-nitrophenyl)butan-1-one(509 mg, 2.4 mmol) and morpholine (0.21 mL, 2.4 mmol) in THF (30 mL) wasadded NaBH(OAc)₃ (0.73 g, 3.4 mmol). The mixture was stirred at RTovernight and washed with HCl (lM). CH₂Cl₂ was added and the layers wereseparated. The aqueous layer was basified to pH 9 using NaOH 1M andextracted with CH₂Cl₂. The organic layer was dried and evaporated thenitro compound. To a solution of the nitro compound (0.50 g, 1.8 mmol)in THF (40 mL) was added AcOH (1.97 mmol, 34.5 mmol) followed by zinc(9.1 g, 137 mmol). The mixture was stirred for 1 h, filtered on Celite®,diluted with H₂O and aqueous NaHCO₃, and the THF layer was evaporated.The residue was extracted with EtOAc, dried and evaporated to give thetitle compound.

PreparationCXXXVII-4-(2,2,2-trifluoro-1-[2-(2-methoxy)ethoxy]-1-(trifluoromethyl)ethyl)phenylamine

[0762] Diethyl azodicarboxylate (366 mg, 2.1 mmol) was added drop-wiseto a solution of 2-(4-aminophenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol(520 mg, 2 mmol), 2-(2-methoxyethoxy)ethan-1-ol (240 mg, 2 mmol) andPPh₃ (550 mg, 2.1 mmol) in THF (10 mL). The mixture was stirred for 2 h,then partitioned between EtOAc and aqueous NaHCO₃ solution. The organicphase was washed with brine. After concentration in vacuo, the organicresidue was purified by flash chromatography on silica to give thecompound. MS: 362 (M+1). Calc'd. for C₁₄H₁₇F₆NO₃-361.29.

Preparation CXXXVIII-2-fluoropyridine-3-carbonyl chloride

[0763] To a solution of 2-fluoropyridine (10 g, 100 mmol) in THF (150mL) under −78° C. was added an LDA solution (2M inheptane/THF/ethylbenzene, 60 mL) dropwise. The mixture was stirred at−78° C. for 3 h, then was quenched with a stream of dry CO₂. Afterwarming to RT, the mixture was partitioned between EtOAc (100 mL) andH₂O (200 mL). The aqueous layer was acidified to pH between 3-4, andextracted with EtOAc. The organic solution was collected and washed withbrine and dried over Na₂SO₄. After removing the solvent in vacuum,2-fluoropyridine-3-carboxylic acid was obtained as a brown oil. MS: 140(M−H). Calc'd. for C₆H₄FNO₂-141.10. 2-Fluoropyridine-3-carboxylic acid(7 g) was suspended in SOCl₂ (100 mL). After heating under reflux for 2h, the mixture became homogeneous. Access SOCl₂ was removed in vacuo toafford a brown solid as desired compound.

Preparation CXXXIX-N-(3-Amino-5-chloro-phenyl)-2-dimethylamino-acetamide

[0764] To a solution of 5-chloro-benzene-1,3-diamine (3 g, 21 mmol) anddimethylamino-acetic acid (2.2 g, 21 mmol) in CH₂Cl₂ (300 mL) was addedEDC (5 g, 25 mmol), HOBt (2.9 g, 21 mmol), and DIEA (5 mL). The reactionmixture was stirred at RT for overnight. Solvent was removed in vacuumand the residue was purified through flash chromatography on silica gel(0-8% MeOH in EtOAc) to give the desired compound.

Preparation CXL-2-amino-4-nitro-benzamide

[0765] To a solution of 2-amino-4-nitro-benzoic acid (9.1 g, 50 mmol) inCH₂Cl₂ (500 mL) was added EDC (12 gram, 60 mmol), HOBt (6.8 g, 50 mmol),DIEA (12 mL), and NH₃ in MeOH (2M, 40 mL). The reaction was stirred atRT for overnight, and a precipitation formed. The solid was isolated viavacuum filtration.

Preparation CXLI-6-nitro-3H-quinazolin-4-one

[0766] 2-Amino-4-nitro-benzamide was suspended in triethyl orthoformate(50 mL) and the mixture was heated to 140° C. for 5 h. Excess reagentwas removed in vacuum. The residue was washed in hexanes to give thecompound as a yellow solid.

Preparation CXLII-6-amino-3H-quinazolin-4-one

[0767] Hydrogenation of 6-nitro-3H-quinazolin-4-one (2 g) in EtOH (200mL) was catalyzed by Pd/c (10%, 200 mg) under a H2 balloon for 1 h. MeOH(200 mL) was added to the mixture. The suspension was filtered through alayer of Celite® and the filtrate was concentrated in vacuum to give thedesired compound.

Preparation CXLIII-(2,4-dinitro-phenyl)-acetic acid methyl ester

[0768] To a solution of (2,4-dinitro-phenyl)-acetic acid (5 g) in MeOH(100 mL) was added concentrated H₂SO₄ (1 mL) and the resulting solutionwas heated at reflux for overnight. After removing solvent in vacuum,the residue was partitioned between EtOAc and aqueous NaHCO₃ (sat.). Theorganic solution was concentrated in vacuum to give the desired compoundwhich was used without further purification.

Preparation CXLIV-6-amino-1,3-dihydro-indol-2-one

[0769] An EtOH solution of (2,4-dinitro-phenyl)-acetic acid methyl esterwas treated with H2 balloon and catalyzed with Pd/c (10%, 500 mg) at RT.The resulting mixture was filtered through a layer of Celite® andconcentrated in vacuum to afford the desired compound.

Preparation CXLVI-3-Methyl-but-2-enoic acid (6-bromo-pyridin-2-yl)-amide

[0770] To a solution of 2-amino-6-bromopyridine (3.015 g, 0.017 mol) andEt₃N (2.40 mL, 0.017 mol) in CH₂Cl₂ (20.0 mL), was added3,3-dimethylacryloylchloride (1.96 mL, 0.017 mol) under N₂ at 0° C. Themixture was slowly warmed to RT and stirred for 12 h. The reaction wasquenched by the addition of H₂O (20.0 mL), the organic layer wasseparated, dried over Na₂SO₄ and evaporated to dryness to yield crudecompound which was used without purification.

Preparation CXLVI-3-Methyl-but-2-enoic acid (6-amino-pyridin-2-yl)-amide

[0771] To a solution of 3-methyl-but-2-enoic acid(6-bromo-pyridin-2-yl)-amide (4.30 g, 0.017 mol) and copper (0.214 g,3.372 mmol) in IpOH (20.0 mL), was added NH₄OH (20.0 mL) in a sealedvessel under N₂. The reaction was sealed and heated to 90° C. for 12 h.The reaction mixture was cooled to RT and EtOAc (50.0 mL) was added. Theorganic layer was separated, and then the aq layer was washed with EtOAc(50.0 mL). Combined organic layers were evaporated to dryness, theresulting residue was dissolved in CH₂Cl₂ (50.0 mL) and washed with H₂O(4×30 mL). The organic layer was dried over Na₂SO₄ and evaporated todryness to yield crude aminopyridine which was used withoutpurification.

PreparationCXLVII-7-Amino-4,4-dimethyl-3,4-dihydro-1H-[1,8]naphthyridin-2-one

[0772] To a mixture of aminopyridine (1.12 g, 5.833 mmol) and AlCl₃(3.11 g, 0.023 mol) was added chlorobenzene (10.0 mL) in a sealed vesselunder Ar. The reaction was sealed and heated to 120° C. for 12 h. Thereaction mixture was cooled to RT and the mixture was poured overice/HCl mixture and extracted with EtOAc (3×50.0 mL). The aqueous layerwas neutralized via addition of solid NaHCO₃ and extracted with EtOAc(5×50 mL). Combined organic layers were dried over Na₂SO₄ and evaporatedto dryness to yield crude compound. Chromatography (Silica gel,CH₂Cl₂:MeOH, 99:1) yielded pure naphthyridin.

PreparationCXLVIII-2-[1-(3-Amino-phenyl)-2,2,2-trifluoro-1-trifluoromethyl-ethoxymethyl]-pyrrolidine-1-carboxylicacid tert-butyl ester

[0773] To a mixture of2-(3-amino-phenyl)-1,1,1,3,3,3-hexafluoro-propan-2-ol (1.30 g),2-hydroxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (1.04 g),PPh₃ (2.64 g) and molecular sieves 4 Å in THF (100 mL) was added diethyldiazocarboxylate (1.55 mL) slowly. The reaction was stirred at RT for 4h and at reflux for overnight. After filtration to remove solids, thefiltrate was concentrated and the residue was taken into Et₂O. Theorganic phase was washed with saturated NaHCO₃ and brine. The organiclayer was dried over MgSO₄ and evaporated to give a crude compound asvery viscous brown oil, which was purified by chromatography throughsilica gel (500 g, 30% to 50% EtOAc in hexanes) to afford2-[1-(3-amino-phenyl)-2,2,2-trifluoro-1-trifluoromethyl-ethoxymethyl]-pyrrolidine-1-carboxylicacid tert-butyl ester as a light brown oil.

Preparation CXLIX-Pyrimidine-4-carbaldehyde oxime

[0774] 9.14 g (97.11 mmol) of 4-methylpyrimidine was slowly added to a0° C. solution of 8.75 g HCl in 40 ml EtOH. To this white suspension wasadded, over 5 min, 61 ml of a 10-20% by weight solution of ethyl nitritein EtOH. The reaction was stirred at 0° C. for 10 min and then at RT for2.5 h. The white salt was filtered and dried under vacuum. The salt wasdissolved into 20 ml H₂O and very slowly treated with about 200 mlsaturated aqueous KHCO₃. A white solid precipitated out of the purplesolution. The solid was filtered and dried under vacuum to yield thetitled compound.

Preparation CL-C-Pyrimidin-4-yl-methylamine dihydrogen chloride

[0775] To a solution of 3.549 g (28.82 mmol) pyrimidine-4-carbaldehydeoxime in 200 ml MeOH was added after degassing with Ar, 800 mg of 10% byweight Pd/C. The mix was stirred under H₂ for 4 h, then filtered througha Celite® plug. The solution was concentrated under vacuum to a volumeof about 50 ml and then treated carefully with 30 ml of 4N HCl indioxane. The mix was concentrated and dried under vacuum to yield thetitled compound as a pink solid.

PreparationCLI-2-(2,4-Dinitro-phenyl)-3,3,3-trifluoro-2-trifluoromethyl-propionicacid methyl ester

[0776] A mixture of 7.08 g (38.07 mmol) 2,4-dinitrofluorobenzene, 2.43 g(41.88 mmol) KF, and 0.58 g (2.21 mmol) 18-crown-6-ether in 37 mlsulfolane was added 4.00 g (19.04 mmol) methyl2-(trifluoromethyl)-3,3,3-trifluoropropionate dropwise over about 7 hvia syringe pump. After the addition was complete, another 2.43 g KF,0.58 g 18-Crown-6-ether were added and then 4.00 g Methyl2-(trifluoromethyl)-3,3,3-trifluoropropionate were added dropwise over12 h. The next day, repeated additions using same amounts and settingsyringe pump addition over 14 h. The following day, the additions wereagain repeated, this time using half the amounts as above additions andsetting syringe pump addition at 12 h. After addition was completed, thereaction mix was cooled to RT and diluted into Et₂O and 0.5N aqueousHCl. The layers were separated, and the organic layer was washed withbrine, dried over Na₂SO₄, filtered and concentrated under vacuum. Thecrude was eluted on a silica gel column with EtOAc/hexanes gradient, toyield the titled compound, as a yellow solid.

[0777] [See Vlasov et al.; J.Org. Chemistry USSR (Engl. Trans.); 15;1979; 1953-1964).]

PreparationCLII-6-Amino-1-hydroxy-3,3-bis-trifluoromethyl-1,3-dihydro-indol-2-one

[0778] To an argon-degassed solution of 5.13 g (13.64 mmol)2-(2,4-dinitro-phenyl)-3,3,3-trifluoro-2-trifluoromethyl-propionic acidmethyl ester in 300 ml EtOH was added 0.5 g of 10% by weight Pd/C. Thereaction was stirred under H₂ overnight and filtered through Celite®,concentrated down, and dried under vacuum, yielding the titled compound.

PreparationCLIII-6-Amino-3,3-bis-trifluoromethyl-1,3-dihydro-indol-2-one

[0779] To a solution of 1.245 g (4.151 mmol)6-amino-1-hydroxy-3,3-bis-trifluoromethyl-1,3-dihydro-indol-2-one in 80ml THF was added 3.565 ml (62.27 mmol) glacial AcOH and 19 g (290.6mmol) Zinc dust (100 mesh). The reaction was stirred 40 min at RT andthen 5 h at reflux. The reaction was cooled to RT. The solvent wasdecanted and concentrated, then dissolved in EtOAc and filtered throughCelite®. The EtOAc solution was then washed with saturated aqueousNaHCO₃ and brine, dried over Na₂SO₄, filtered, and concentrated anddried under vacuum, to yield the titled compound, as a yellow solid.

PreparationCLIV-N-[3-(2-Amino-ethoxy)-4-pentafluoroethyl-phenyl]-2-chloro-nicotinamide

[0780] To a solution of 500 mg (0.98 mmol)Boc-N-[3-(2-Amino-ethoxy)-4-pentafluoroethyl-phenyl]-2-chloro-nicotinamidein 10 ml CH₂Cl₂ was added 10 ml TFA and stirred for 2 h. The reactionwas concentrated down, treated with 6N aqueous NaOH, and extracted 3times with CH₂Cl₂. The combined organic extracts were dried over Na₂SO₄,filtered, concentrated down, and dried under vacuum, yielding the titledcompound.

PreparationCLV-2-Chloro-N-[3-(2-methanesulfonylamino-ethoxy)-4-pentafluoroethyl-phenyl]-nicotinamide

[0781] To a solution of 381 mg (0.93 mmol)N-[3-(2-amino-ethoxy)-4-pentafluoroethyl-phenyl]-2-chloro-nicotinamidein 10 ml CH₂Cl₂ at 0° C. was added 0.389 ml Et₃N and 0.072 ml (0.93mmol) methanesulfonylchloride. After 5 min, the reaction was stirred atRT for 30 min. The reaction was diluted with CH₂Cl₂, washed with brine,dried over Na₂SO₄, filtered, concentrated, and dried under vacuum,yielding the titled compound as a white foamy solid.

Preparation CLVI-2-Methyl-2-(4-nitro-phenyl)-propionic acid

[0782] To a solution of 2-(4-nitro-phenyl)-propionic acid (50 g, 0.26mole) in 250 mL of MeOH was added 6 mL of concentrated HCl. Theresulting solution was heated at reflux for 16 h. Then the resultantmixture was diluted with 200 mL of aq. NaHCO₃ and 500 mL of EtOAc. Theorganic layer was separated, dried over Na₂SO₄, and concentrated. Theresidue was diluted with 100 mL of THF and added to a suspension of NaH(11.2 g, 0.28 mole, 60% in mineral oil) in 600 mL of THF. To theresulting mixture was added CH₃I (18.3 mL, 0.29 mole) in one portion.The resulting mixture was stirred for 48 h at 40° C., then was dilutedwith aq. NH₄Cl solution and EtOAc. The organic layer was separated,dried over Na₂SO4, and concentrated. The residue was used withoutfurther purification.

[0783] To a solution of the residue (54 g, 0.24 mole) in 500 ml of MeOHwas added 5N aq. NaOH (144 mL, 0.72 mole). The mixture was stirred for16 h at 40° C. The resulting mixture was concentrated, the residue wasdiluted with H₂O (500 mL), and acidified with 2N HCl to give aprecipitate. The precipitate was filtered and dried to give the titledcompound as a yellowish solid. MS: 210 (M+1), Calc'd forC₁₀H₁₂NO₄-210.20.

PreparationCLVII-2-Methyl-5-[1-methyl-1-(4-nitro-phenyl)-ethyl]-[1,3,4]oxadiazole

[0784] A mixture of 2-methyl-2-(4-nitro-phenyl)-propionic acid (5 g, 24mmol.) and a few drops of DMF in SOCl₂ was stirred at reflux for 16 h.The resulting solution was concentrated to give corresponding acidchloride as a brown solid. To a mixture of the acid chloride (2.33 g,10.2 mmol), acetic acid hydrazide (0.91 g, 12.2 mmol.), Et₃N (2.86 mL,20.2 mmol.) in CH₂Cl₂ (50 mL) was added 2 crystals of DMAP at RT. Themixture was stirred for 16 h and concentrated. A solution of the residuein 50 mL of phosphorous oxychloride was heated at 95° C. for 16 h. Themixture was concentrated and diluted with ice-water and EtOAc. Theorganic layer was washed with saturated aq. NaHCO₃ solution twice, driedover Na₂SO₄, and concentrated. The residue was purified by SiO₂chromatography (hexane:EtOAc=1:1) to give the titled compound as a paleyellow crystal. MS: 248 (M+1), Calc'd for C₁₂H₁₄N₃O₃-248.10.

PreparationCLVIII-2-Methyl-5-[1-methyl-1-(4-amino-phenyl)-ethyl]-[1,3,4]oxadiazole

[0785] A mixture of2-methyl-5-[1-methyl-1-(4-nitro-phenyl)-ethyl]-[1,3,4]oxadiazole (1.36g, 5.5 mmol.) and Pd/C (68 mg) in EtOAc (50 mL), was stirred under 1 atmof H₂ for 16 h. The resultant was filtered over Celite®, and thefiltrate was concentrated to give the titled compound as a pale yellowcrystalline. MS: 218 (M+1) calc'd for C₁₂H₁₆N₃O-218.12.

Preparation CLIX-4-[1-Methyl-1-(4-nitro-phenyl)-ethyl]-pyrimidine

[0786] To a mixture of 1-(4-nitro-phenyl)-propan-2-one (5.32 g, 29.7mmol.), triethylbenzylammonium chloride (0.34 g, 1.5 mmol.), and 13 mLof aq. 5N KOH solution (65.3 mmol.) in CH₂Cl₂ was added CH₃I (4.06 mL,65.3 mmol.). The resulting mixture was stirred at 40° C., and thendiluted with EtOAc and H₂O. The organic layer was dried andconcentrated. To the residue (1.0 g, 4.8 mmol.) in toluene (30 mL) wasadded dimethylformamide dimethylacetal (1.27 mL, 9.6 mmol.). Theresulting mixture was heated at reflux for 6 h then concentrated to give1-dimethylamino-4-methyl-4-(4-nitro-phenyl)-pent-1-en-3-one as a yellowsolid (MS 263 (M+1) Calc'd for C¹⁴H₁₉N₂O₃-263.13).

[0787] A mixture of1-dimethylamino-4-methyl-4-(4-nitro-phenyl)-pent-1-en-3-one (0.5 g, 1.9mmol.), formamidine HCl (0.305 g, 3.8 mmol.), and NaOEt (1.29 g, 4.0mmol) was heated in Smith synthesizer under microwave for 10 min at 150°C. The resultant mixture was diluted with H₂O and EtOAc. The organiclayer was dried, and the residue was used without further purification.MS: 244 (M+1) Calc'd for C₁₃H₁₄N₃O₂-244.10.

Preparation CLX-5-[1-Methyl-1-(4-nitro-phenyl)-ethyl]-1H-pyrazole

[0788] A mixture of1-dimethylamino-4-methyl-4-(4-nitro-phenyl)-pent-1-en-3-one (0.36 g, 1.4mmol.) and hydrazine hydrate (1.0 g, 6.25 mmol.) in EtOH was heated at50° C. for 3h. The mixture was concentrated, and the residue was dilutedwith H₂O and EtOAc. The organic layer was dried over Na₂SO₄ andconcentrated to give the titled compound as a yellow solid. MS: 232(M+1) Calc'd for C₁₂H₁₄N₃O₂-232.10.

Preparation CLXI-2-tert-Butyl-5-nitro-phenylamine

[0789] Concentrated H₂SO₄ (1 L) was cooled to −10° C. with a dry iceIpOH bath in a 2 L 3-neck round bottom flask fitted with a mechanicalstirrer and temperature probe. 2-t-Butylaniline (109 g, 730 mmol) wasadded, giving a clumpy solid. Once the temperature of the mixture wasstabilized at −10° C., KNO₃ (101 g, 1001 mmol) was added portion-wise,as the solid, over 4 h, maintaining the temperature between −20 and −5°C. Once all of the KNO₃ was added, the reaction was stirred overnightwith gradual warming to RT. The reaction was quenched by diluting withH₂O and extracting 3× with EtOAc. The EtOAc extracts were washedmultiple times with saturated NaHCO₃ (aq), until gas evolution ceased,then with brine. The EtOAc extracts were combined, dried over anhydrousNa₂SO₄, filtered and concentrated under reduced pressure giving a blackoil. The oil was eluted through a 36×7 cm column of silica gel with a5%; 10%; 15%; 25%; and 50% EtOAc:Hexanes step gradient (2 L each step)giving 2-tert-butyl-5-nitro-phenylamine as a red solid.

Preparation CLXII-2-Bromo-N-(2-tert-butyl-5-nitro-phenyl)-acetamide

[0790] 2-tert-Butyl-5-nitro-phenylamine (70 g, 359 mmol) and a catalyticamount of DMAP were dissolved in THF (1.5 L) under N₂. TEA (109 g, 1077mmol) was added and the solution was cooled to 0° C. Bromoacetyl bromide(207 g, 1023 mmol) was added and the reaction was gradually warmed to RTwith stirring overnight. The reaction was partially concentrated underreduced pressure, treated with H₂O and extracted with EtOAc (3×). TheEtOAc extracts were washed with brine, combined, dried over anhydrousNa₂SO₄, filtered and concentrated under reduced pressure giving a blackoil. This oil was eluted through a 38×7 cm column of silica gel with95:5:0.5 CH₂Cl₂:MeOH:NH₄OH_((aq)) eluant giving2-bromo-N-(2-tert-butyl-5-nitro-phenyl)-acetamide as a brown solid.

PreparationCLXIII-N-(2-tert-Butyl-5-nitro-phenyl)-2-dimethylamino-acetamide

[0791] 2-Bromo-N-(2-tert-butyl-5-nitro-phenyl)-acetamide (80 g, 253mmol) and K₂CO₃ (70 g, 506 mmol) were combined in a 3-L 3-neck roundbottom flask fitted with a mechanical stirrer, N₂ inlet, and pressureequalizing addition funnel. THF (1.75 L) was added and the mixture wascooled to 0° C. under N₂. DMA (400 mL of a 2 M solution in THF, 800mmol) was added to the mixture through the pressure equalizing additionfunnel over 30 min. The mixture was gradually warmed to RT with stirringovernight. The reaction was quenched by filtering it under vacuum andthen concentrating the filtrate under reduced pressure. The recoveredmaterial was eluted through a 36×7 cm column of silica gel with 50%EtOAc:Hexanes givingN-(2-tert-butyl-5-nitro-phenyl)-2-dimethylamino-acetamide as a brownsolid.

[0792] The pyrolidino and morpholino analogs are prepared bysubstituting the dimethylamine with respectively pyrolidine ormorpholine and using the same chemistry as described.

[0793] a) N-(2-tert-Butyl-5-nitro-phenyl)-2-pyrrolidin-1-yl-acetamide.

[0794] b) N-(2-tert-Butyl-5-nitro-phenyl)-2-morpholin-4-yl-acetamide.

PreparationCLXIV-N-(5-Amino-2-tert-butyl-phenyl)-2-dimethylamino-acetamide

[0795] N-(2-tert-Butyl-5-nitro-phenyl)-2-dimethylamino-acetamide (25.8g, 92 mmol) was dissolved in EtOH (1.4 L) and 1,4-dioxane (200 mL). Thesolution was degassed under vacuum with stirring. 10% Pd/C (2.5 g) wasadded (as a slurry in EtOH). The mixture was degassed again, then thereaction vessel was charged with H₂ gas (balloon) and stirred overnightat RT. The reaction was filtered through Celite® with MeOH and thefiltrate was concentrated under reduced pressure. The recovered materialwas eluted through a 36×7 cm column of silica gel with a 97.5:2.5:0.25and 95:5:0.5 CH₂Cl₂:MeOH:NH₄OH_((aq)) step gradient givingN-(5-amino-2-tert-butyl-phenyl)-2-dimethylamino-acetamide as a brownsolid.

Preparation CLXV-5-Chloro-1-methyl-1H-pyrazole-4-carboxylic acid(4-tert-butyl-phenyl)-amide

[0796] 5-Chloro-1-methyl-1H-pyrazole-4-carbonyl chloride (1.0 g, 5.6mmol) was dissolved in CH₂Cl₂ (100 mL) under N₂ and cooled to 0° C.4-t-Butylaniline was added and the reaction was stirred with gradualwarming to RT overnight. The reaction was quenched with saturatedNaHCO₃(aq) and extracted 3× with fresh CH₂Cl₂. The CH₂Cl₂ extracts werewashed with brine, combined, dried over anhydrous Na₂SO₄, filtered andconcentrated under reduced pressure giving5-chloro-1-methyl-1H-pyrazole-4-carboxylic acid(4-tert-butyl-phenyl)-amide as a foamy pink solid.

Preparation CLXVI-1,2-dihydro-3-spiro-1′-cyclopropyl-1H-indole

[0797] A solution of 3-(2-bromo-ethyl)-1H-indole (5 g) in anhydrousCH₃CN (100 mL) was suspended with oven dried K₂CO₃ (20 g) and heated toreflux for 10 h. After cooling to RT, the mixture was filtered and thefilter cake was washed with EtOH (50 mL). The combined filtrate wastreated with NaBH₄ (300 mg) and stirred for 3 h at RT. Solvents wereremoved in vacuo and the residue was partitioned between H₂O (160 mL)and EtOAc (60 mL). The organic layer was extracted with aqueous HCl(0.5N, 30 mL×2). The acid layer was basified with NH₄OH (aq. Conc.) andextracted with EtOAc. The organic phase was washed with brine and driedover Na₂SO₄ and concentrated to give the desired compound as a colorlessthin oil.

Preparation CLXVII-6-nitro-1,2-dihydro-3-spiro-1′-cyclopropyl-1H-indole

[0798] 1′,2′-Dihydrospiro(cyclopropane-1,3′-[3H]indole) (1.8 g 12.4mmol) was added in dropwise over a period of 20 min to a cooled (−5 to−10° C.) solution of NaNO₃ (1.3 g) in H₂SO₄ (conc., 30 mL). After theaddition, the reaction was stirred for another 40 min., then the mixturewas poured onto crushed ice (200 g) and the resulting mixture wasbasified with NH₄OH (aq., conc.) with cooling. The basified mixture wasextracted with EtOAc twice and the organic layer was washed with brinethen dried over Na₂SO₄. After concentration in vacuo, the compound wasisolated as a dark gray solid.

Preparation CLXVIII-Ethyl6-nitro-1,2-dihydro-3-spiro-1′-cyclopropyl-1H-indole-1-carbamate

[0799] A solution of6-nitro-1,2-dihydro-3-spiro-1′-cyclopropyl-1H-indole (2.7 g) in CH₂CL₂(100 mL) was suspended with NaHCO₃ (5 g), and ethyl chloroformate wasadded dropwise with vigorous stirring. After the addition, the reactionwas stirred overnight. The mixture was washed with H₂O (100 mL), thendried over Na₂SO₄ and concentrated in vacuo. The residue wasrecrystalized in MeOH to give the title compound as a dark graycrystalline.

Preparation CLXIX-Ethyl6-amino-1,2-dihydro-3-spiro-1′-cyclopropyl-1H-indole-1-carbamate

[0800] Ethyl6-nitro-1,2-dihydro-3-spiro-1′-cyclopropyl-1H-indole-1-carbamate (2.1 g)was dissolved in EtOH (200 mL), suspended with Pd/C (10%, 560 mg) andequipped with a balloon filled with H₂. The hydrogenation was finishedin 3 h. The reaction mixture was filtered through a layer of Celite®.The filtrate was concentrated in vacuo to give the desired product as awhite solid.

PreparationCLXX-4-[1-Methyl-1-(4-nitro-phenyl)-ethyl]-3,6-dihydro-2H-pyridine-1-carboxylicacid ethyl ester

[0801]1-Methyl-4-[1-methyl-1-(4-nitro-phenyl)-ethyl]-1,2,3,6-tetrahydro-pyridine(5.2 g) was dissolved in toluene (100 mL) and ethyl chloroformate (2.4g). The mixture was heated at reflux for overnight and cooled to RT. Thetoluene solution was washed with NaHCO₃ (aq., sat., 100 mL) then brine(100 mL) and dried over Na₂SO₄. The organic phase was concentrated invacuo to give the desired compound which was used without purification.

PreparationCLXXI-4-[1-Methyl-1-(4-amino-phenyl)-ethyl]-3,6-dihydro-2H-pyridine-1-carboxylicacid ethyl ester

[0802]4-[1-Methyl-1-(4-nitro-phenyl)-ethyl]-3,6-dihydro-2H-pyridine-1-carboxylicacid ethyl ester was dissolved in EtOH (150 mL) and suspended with Pd/C(10%, 1 g). The reaction flask was equipped with a balloon filled withH₂. The hydrogenation was continued for 3 days. The mixture was filteredthrough a layer of Celite® and concentrated in vacuo to provide thedesired compound as a light brown oil.

Preparation CLXXII: 3,3-dimethyl-6-nitroindoline 3-Methyl-but-2-enoicacid (3-acetylamino-phenyl)-amide

[0803] 3,3-Dimethylacryloyl chloride (3.3 ml, 29.3 mmol) was added to amixture of 3′-aminoacetanilide (4.40 g, 29.3 mmol) and Et₃N (4.5 ml,32.2 mmol) in 50 ml of CH₂Cl₂ and 25 ml of THF at 0° C. under N₂. Themixture was stirred at RT overnight, diluted with 100 ml of CH₂Cl₂,washed with aqueous Na₂CO₃, then brine, condensed, and purified by flashcolumn chromatography (15 to 30% of EtOAc in CH₂Cl₂). The titledcompound was obtained as an off-white solid. MS (ES⁺): 233.1 (M+H)⁺.Calc'd for C₁₃H₁₆N₂O₂-232.28.

[0804] The following compounds were prepared similarly to the procedureoutlined above:

[0805] a) 3-Methyl-but-2-enoic acid phenylamide. MS(ES⁺): 176.1 (M+H)⁺.Calc'd for C₁₁H₁₃NO-175.23.

PreparationCLXXIII-N-(4,4-Dimethyl-2-oxo-1,2,3,4-tetrahydro-quinolin-7-yl)-acetamide

[0806] The mixture of 3,3-dimethyl-6-nitroindoline 3-Methyl-but-2-enoicacid (3-acetylamino-phenyl)-amide (1.05 g, 4.52 mmol) and AlCl₃ (5.0 g,37.5 mmol, Aldrich, 99.99%) in 50 ml of anhydrous chlorobenzene wasstirred at 120° C. (oil bath temperature) under N₂ overnight, cooled toRT, poured into 10 ml of ice cold HCl, stirred for 30 min, and extractedwith EtOAc. The organic portions were combined, washed with brine, driedwith Na₂SO₄, filtered, condensed, and purified by flash columnchromatography (1% of MeOH in CH₂Cl₂). The titled compound was obtainedas an off-white solid. MS (ES⁺): 233.2 (M+H)⁺. Calc'd forC₁₃H₁₆N₂O₂-232.28.

[0807] The following compounds were prepared similarly to the procedureoutlined above:

[0808] a) 4,4-Dimethyl-3,4-dihydro-1H-quinolin-2-one MS(ES⁺): 175.6(M+H)⁺. Calc'd for C₁₁H₁₃NO-175.23.

Preparation CLXXIV: 7-Amino-4,4-dimethyl-3,4-dihydro-1H-quinolin-2-one

[0809] N-(4,4-Dimethyl-2-oxo-1,2,3,4-tetrahydro-quinolin-7-yl)-acetamide(1.50 g, 6.46 mmol) in 10 ml of HCl (concentrated, 37%) and 30 ml ofEtOH was stirred at 75° C. for 4 h. The solvents were removed underreduced pressure. The residue was dissolved in EtOAc/H₂O, neutralizedwith NaHCO₃, washed with brine, dried with Na₂SO₄, filtered, andcondensed to give the titled compound as an off-white solid. MS (ES⁺):191.2 (M+H)⁺. Calc'd for C₁₁H₁₄N₂O-190.24.

Preparation CLXXV-4,4-Dimethyl-1,2,3,4-tetrahydro-quinolin-7-ylamine

[0810] The mixture of 7-amino-4,4-dimethyl-3,4-dihydro-1H-quinolin-2-one(1.07 g, 5.62 mmol) and borane dimethylsulfide complex (1.60 ml, 16.9mmol)in 40 ml of anhydrous THF was heated at reflux under N₂ for 15 h.The solvents were removed under reduced pressure. The residue was heatedat reflux in 20 ml of MeOH for 2 h, then 0.80 g of NaHCO₃ was added, andthe mixture was heated at reflux for 2 h. The mixture was filtered,condensed, and the residue was purified by flash column chromatography(5 to 10% of EtOAc in CH₂Cl₂). The titled compound was obtained as aviscous oil. MS(ES⁺): 176.9 (M+H)⁺. Calc'd for C₁₁H₁₆N-176.26.

[0811] The following compounds were prepared similarly to the procedureoutlined above:

[0812] a) 4,4-Dimethyl-1,2,3,4-tetrahydroquinoline MS(ES⁺) 162.5 (M+H)⁺.Calc'd for C₁₁H₁₅N-161.24.

PreparationCLXXVI-N-(4,4-Dimethyl-1,2,3,4-tetrahydro-quinolin-7-yl)-2-fluoronicotinamide

[0813] The mixture of 4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-7-ylamine(0.20 g, 1.13 mmol), 2-fluoronicotinic acid (0.16 g, 1.13 mmol), TBTU(0.36 g, 1.13 mmol), and DIEA (0.24 ml, 1.36 mmol) in 5 ml of DMF wasstirred at RT for 3 h, then partitioned between EtOAc and Na₂CO₃ (aq).The organic layer was washed with H₂O, brine, dried with MgSO₄,filtered, condensed, and the residue was purified by flash columnchromatography (20 to 30% of EtOAc in CH₂Cl₂).

[0814] The titled compound was obtained as an off-white solid. MS (ES⁺):300.1 (M+H)⁺. Calc'd for C₁₇H₁₈FN₃O-299.34.

[0815] The following compounds were prepared similarly to the procedureoutlined above:

[0816] a)N-(4,4-Dimethyl-2-oxo-1,2,3,4-tetrahydro-quinolin-7-yl)-2-fluoronicotinamide,as an off-white solid. MS (ES⁺): 314.2 (M+H)⁺. Calc'd forC₁₇H₁₆FN₃O₂-313.33.

[0817] b)N-(1-Ethyl-4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-7-yl)-2-fluoronicotinamide,MS(ES⁺): 328.3 (M+H)⁺. Calc'd for C₁₉H₂₂FN₃O-327.40.

Preparation CLXXVII-4,4-Dimethyl-7-nitro-1,2,3,4-tetrahydro-quinoline

[0818] To 13 ml of H₂SO₄ (96%) cooled in a salt ice bath was addeddropwise 4,4-dimethyl-1,2,3,4-tetrahydro-quinoline (5.80 g, 36.0 mmol).The resulting slurry was stirred for 30 min, upon when concomitantaddition of HNO₃ (90%, 1.70 ml, 36.0 mmol) and H₂SO₄ (96%, 7 ml) wasstarted, the addition was finished in 20 min, the mixture was stirred at0° C. to 15° C. for 2 h, poured into ice, and extracted with EtOAc. Theorganic portion was washed with brine, condensed, and purified by flashcolumn chromatography (0 to 10% of EtOAc in hexanes). The titledcompound was obtained as a yellow oil. MS (ES⁺): 206.9 (M+H)⁺. Calc'dfor C₁₁H₁₄N₂O₂-206.24.

PreparationCLXXVIII-1-Ethyl-4,4-dimethyl-7-nitro-1,2,3,4-tetrahydroquinoline

[0819] The mixture of 4,4-dimethyl-7-nitro-1,2,3,4-tetrahydro-quinoline(0.48 g, 2.33 mmol), iodoethane (0.21 ml, 2.56 mmol), and NaH (60%, 0.10g, 2.5 mmol) in 10 ml of DMF was stirred at RT overnight, andpartitioned between EtOAc and H₂O. The combined organic portions werewashed with brine, dried with MgSO₄, filtered, and condensed. The crudecompound was purified by flash column chromatography (5 to 10% of CH₂Cl₂in hexanes). The titled compound was obtained as a yellow oil. MS (ES⁺):235.3 (M+H)⁺. Calc'd for C₁₃H₁₈N₂O₂-234.29.

Preparation CLXXIX:1-Ethyl-4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-7-ylamine

[0820] The mixture of1-ethyl-4,4-dimethyl-7-nitro-1,2,3,4-tetrahydro-quinoline (0.28 g) andPd/C (0.060 g, 10% wt)in 10 ml of EtOAc was placed under H₂ which wasprovided by a balloon and stirred at RT overnight. Then the mixture wasfiltered through Celite®, condensed, and the residue was purified byflash column chromatography (2% of EtOAc in CH₂Cl₂). The titled compoundwas obtained as a pink oil. MS(ES⁺) 204.8 (M+H)⁺. Calc'd forC₁₁H₁₆N-204.31.

Preparation CLXXX-1-(4-Nitro-phenyl)-cyclopropanecarbonitrile

[0821] NaOH (5.0 N, 80 ml) was added to a mixture of4-nitrophenylacetonitrile (10.0 g, 61.7 mmol), 1,2-dibromoethane (8.0ml, 92.5 mmol), and tetraethylammonium chloride hydrate (10.2 g, 61.7mmol) in 200 ml of CH₂Cl₂ at RT. The resulting mixture was stirred at RTfor 24 h, diluted with CH₂Cl₂, and acidified with HCl (10%, aq). Theorganic layer was separated, washed with brine, condensed, and the crudewas purified by flash column chromatography. The titled compound wasobtained as a light yellowish solid.

Preparation CLXXXI-C-[1-(4-Nitro-phenyl)-cyclopropyl]-methylamine

[0822] The mixture of 1-(4-nitro-phenyl)-cyclopropanecarbonitrile (3.0g, 15.9 mmol) and borane THF complex (1.0 M solution in THF, 32 ml, 32mmol) in 50 ml of anhydrous THF was heated at reflux overnight. Themixture was cooled to RT, quenched with 2.5 ml of 50% AcOH aqueoussolution, then partitioned between EtOAc and NaHCO₃ (aq). The combinedorganic portions were washed with brine, dried with MgSO₄, filtered, andcondensed. The crude was purified by flash column chromatography (1 to2% of MeOH in CH₂Cl₂). The titled compound was obtained as a lightbrownish solid. MS (ES⁺): 192.9. Calc'd for C₁₀H₁₂N₂O₂-192.2.

PreparationCLXXXII-2,2,2-Trifluoro-N-[1-(4-nitro-phenyl)-cyclopropylmethyl]-acetamide

[0823] Trifluoroacetic anhydride (5.26 ml, 36.9 mmol) was added to amixture of C-[1-(4-nitro-phenyl)-cyclopropyl]-methylamine (2.37 g, 12.3mmol) and triethyl amine (8.6 ml, 61.5 mmol) in 50 ml of CH₂Cl₂ at RT.The resulting mixture was stirred for 2 h. The volatiles were removedunder reduced pressure and the residue was partitioned between EtOAc andaqueous NaHCO₃. The organic layer was washed with brine, dired withMgSO₄, filtered, and condensed. The crude compound was purified by flashcolumn chromatography (10 to 20% of EtOAc in hexanes), and the titledcompound was obtained as an off-white solid.

PreparationCLXXXIII-1-(7-Nitro-4-spiro-1′-cyclopropane-3,4-dihydro-1H-isoquinolin-2-yl)-2,2,2-trifluoroethanone

[0824] A mixture of2,2,2-trifluoro-N-1-(4-nitro-phenyl)-cyclopropylmethyl]-acetamide (3.10g, 10.7 mmol) and paraformaldehyde (0.54 g, 17.2 mmol) was added to amixture of 12 ml of glacial AcOH and 20 ml of H₂SO4 at RT. The resultingmixture was stirred at 40° C. for 12 h, poured into ice-water andextracted with EtOAc. The combined organic portion was washed withNaHCO₃ (aq), H₂O, brine, then dried with MgSO₄, and condensed. The crudecompound was purified by flash column chromatography (10 to 20% of EtOAcin hexanes), and the titled compound was obtained as a white solid.

PreparationCLXXXIV-7-Nitro-4-spiro-1′-cyclopropane-1,2,3,4-tetrahydroisoquinoline

[0825] A mixture of1-(7-nitro-4-spiro-1′-cyclopropane-3,4-dihydro-1H-isoquinolin-2-yl)-2,2,2-trifluoroethanone(0.32 g, 1.07 mmol) and K₂CO₃ (1.50 g, 14.2 mmol) in 7 ml of MeOH and 2ml of H₂O was stirred at RT overnight. The mixture was filtered, and thefiltrate was concentrated. The residue was dissolved in EtOAc, washedwith NH₄Cl (aq), brine, dried with MgSO₄, filtered, and condensed togive the titled compound as a light yellowish solid. MS (ES⁺): 204.9(M+H)⁺. Calc'd for C₁₁H₁₂N₂O₂-204.23.

Preparation CLXXXV-tert-ButylN-[7-nitro-4-spiro-1′-cyclopropane-3,4-dihydro-1H-isoquinoline-2-carbamate

[0826] The mixture of7-nitro-4-spiro-1′-cyclopropane-1,2,3,4-tetrahydroisoquinoline (0.20 g,0.98 mmol), BOC₂O (0.24 g, 1.08 mmol), DMAP(0.025 g, 0.20 mmol), DIEA(0.51 ml, 2.94 mmol) in 10 ml of CH₂Cl₂ was stirred at RT for 2 h. Thesolvent was removed, the residue was purified by flash columnchromatography (5 to 10% of EtOAc in hexanes), and the titled compoundwas obtained as a white solid.

Preparation CLXXXVI: tert-ButylN-[7-amino-4-spiro-1′-cyclopropane-3,4-dihydro-1H-isoquinoline]carbamate

[0827] A mixture of tert-butylN-[7-nitro-4-spiro-1′-cyclopropane-3,4-dihydro-2H-isoquinoline-2-carbamate(0.27 g, 0.89 mmol) and Pd/C (0.05 g, 10% wt) in 15 ml of MeOH wasplaced under H₂ which was provided by a balloon and stirred at RT for1.5 h. The mixture was filtered through Celite®, and condensed to givethe titled compound as a white solid. MS (ES⁺): 274.8 (M+H)⁺. Calc'd forC₁₆H₂₂N₂O₂-274.36.

PreparationCLXXXVII-4-methyl-6-[2-(1-methyl-ppyrrolidin-2-yl)-ethyl]-pyrimidin-2-ylamine

[0828] To a solution of (S)-(−)-1-methyl-2-pyrrolidine (320 mg, 2.78mmol) in dry THF (10 mL) at 0° C. was added NaH (167 mg, 4.16 mmol).After stirred at RT for 1 h, 2-amino-4-chloro-6-methylpyrimidine (600mg, 4.16 mmol) in dry THF (10 mL) was added dropwise via the additionfunnel. The resulting mixture was heated to reflux under Ar gas for 20h. The reaction was cooled to RT and quenched with sat. NH₄Cl. Solventwas removed. The residue was partitioned between H₂O and CHCl₃. Theorganic layer was washed with H₂O, brine, dried over MgSO₄, andevaporated to dryness. This crude compound was purified in column elutedwith CH₂Cl₂:MeOH=95%:5% to yield the title compound. MS m/z: 223.2(M+H). Calc'd. for C₁₂H₂₀N₄-222.2.

Preparation CLXXXVIII-(6-bromo-pyridin-2-yl)3-Methyl-but-2-enoic-amide

[0829] To a solution of 2-amino-6-bromopyridine (4, 3.015 g, 0.017 mol)and Et₃N (2.40 mL, 0.017 mol) in CH₂Cl₂ (20.0 mL), was added3,3-dimethylacryloylchloride (1.96 mL, 0.017 mol) under N₂ at 0° C. Thereaction mixture was slowly warmed to RT and stirred for 12 h. Thereaction was quenched by the addition of H₂O (20.0 mL). The organiclayer was separated, dried over Na₂SO₄and evaporated to dryness to yieldcrude compound which was used without purification.

Preparation CLXXXIX-(6-amino-pyridin-2-yl) 3-Methyl-but-2-enoic-amide

[0830] To a solution of 2-amino-6-bromopyridine (4.30 g, 0.017 mol) andcopper (0.214 g, 3.372 mmol) in IPOH (20.0 mL), was added NH₄OH (20.0mL) in a sealed vessel under N₂. The reaction was sealed and heated to90° C. for 12 h. The mixture was cooled to RT and EtOAc (50.0 mL) wasadded. The organic layer was separated, and the aq layer was washed withEtOAc (50.0 mL). The combined organic layers were evaporated to dryness,the resulting residue was dissolved in CH₂Cl₂ (50.0 mL) and washed withH₂O (4×30 mL). The organic layer was dried over Na₂SO₄ and evaporated todryness to yield crude compound which was used without purification.

PreparationCXC-7-Amino-4,4-dimethyl-3,4-dihydro-1H-[1,8]naphthyridin-2-one

[0831] To a mixture of aminopyridine 6 (1.12 g, 5.833 mmol) and AlCl₃(3.11 g, 0.023 mol) was added chlorobenzene (10.0 mL) in a sealed vesselunder Ar. The reaction was sealed and heated to 120° C. for 12 h. Thereaction mixture was cooled to RT and the mixture was poured overice/HCl mixture and extracted with EtOAc (3×50.0 mL). The Aq layer wasneutralized with solid NaHCO₃ and extracted with EtOAc (5×50 mL). Thecombined organic layers were dried over Na₂SO₄ and evaporated to drynessto yield crude compound which was purified by chromatography (Silicagel, CH₂Cl₂:MeOH, 99:1) yielding the title compound.

PreparationCXCI-2-[1-(3-Amino-phenyl)-2,2,2-trifluoro-1-trifluoromethyl-ethoxymethyl]-pyrrolidine-1-carboxylicacid tert-butyl ester

[0832] To a mixture of2-(3-amino-phenyl)-1,1,1,3,3,3-hexafluoro-propan-2-ol (1.30 g),2-hydroxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (1.04 g),PPh₃ (2.64 g) and molecular sieves 4 Å in THF (100 mL) was added DEAD(1.55 mL) slowly. The reaction was stirred at RT for 4 h and at refluxovernight. After filtration to remove solids, the filtrate wasconcentrated and the residue was taken up into Et₂O. The organic phasewas washed with saturated NaHCO₃ and brine. The organic layer was driedover MgSO₄ and evaporated to give a very viscous brown oil, which waspurified by chromatography through silica gel (500 g, 30% to 50% EtOAcin hexanes) to afford2-[1-(3-amino-phenyl)-2,2,2-trifluoro-1-trifluoromethyl-ethoxymethyl]-pyrrolidine-1-carboxylicacid tert-butyl ester as a light brown oil.

Preparation CXCII-N-(3-Amino-5-chloro-phenyl)-2-dimethylamino-acetamide

[0833] To a solution of 5-chloro-benzene-1,3-diamine (3 g, 21 mmol) anddimethylamino-AcOH (2.2 g, 21 mmol) in CH₂Cl₂ (300 mL) was added EDC (5g, 25 mmol), HOBt (2.9 g, 21 mmol), and DIEA (5 mL). The reactionmixture was stirred at RT overnight. Solvent was removed in vacuo andthe residue was purified through flash chromatography on silica gel(0-8% MeOH in EtOAc) to give the desired compound.

General Procedure for the preparation of 2,6-diamonipyridines

[0834] To a solution of 2-amino-6-bromopyridine (1.070 g, 6.061 mmol) in2,4-dimethylphenol (2.0 mL) was added amine (6.667 mmol) and thereaction mixture was heated to 150° C. for 12 h. The mixture was cooledto RT and aq. HCl (2.0 M, 30 mL) was added. EtOAc (50 mL) was added andthe organic layer was separated. The Aq layer was washed with EtOAc(2×40 mL) and the combined organic layers were washed with H₂O (50 mL),dried over Na₂SO₄, concentrated under vacuo to yield crude compoundwhich was used without purification.

[0835] The following compounds were prepared similarly to the procedureoutlined above:

[0836] a) 3,4,5,6-Tetrahydro-2H-[1,2′]bipyridinyl-6′-ylamine:

[0837] b) 6-(4-Methyl-piperazin-1-yl)-pyridin-2-ylamine:

Preparation CXCIII-2-Methyl-2-(4-nitrophenyl)propionic acid

[0838] To a solution of 2-(4-nitrophenyl)propionic acid (50 g, 0.26 mol)in 250 mL of MeOH was added 6 mL of concentrated HCl. The resultingsolution was heated at reflux for 16 h. The reaction was diluted with200 mL of aq. NaHCO₃ and 500 mL of EtOAc. The organic layer wasseparated, dried over Na₂SO₄, and concentrated. The residue was dilutedwith 100 mL of THF and added to a suspension of NaH (11.2 g, 0.28 mol,60% in mineral oil) in 600 mL of THF. To the resulting mixture was addedCH₃I (18.3 mL, 0.29 mol) in one portion. The resulting mixture wasstirred for 48 h at 40° C. and diluted with aq. NH₄Cl solution andEtOAc. The organic layer was separated, dried over Na₂SO4, andconcentrated. The residue was used without further purification.

[0839] To a solution of the residue (54 g, 0.24 mol) in 500 mL of MeOHwas added 5 N aq. NaOH solution (144 mL, 0.72 mol). The mixture wasstirred for 16 h at 40° C., then, concentrated, and the residue wasdiluted with H₂O (500 mL). The aq. solution was acidified with 2N HCl togive a precipitate which was filtered and dried to give the titledcompound as a yellowish solid. MS: (ES+) 210 (M+H). Calc'd forC₁₀H₁₂NO₄-210.20.

PreparationCXCIV-2-Methyl-5-[1-methyl-1-(4-nitro-phenyl)-ethyl]-[1,3,4]oxadiazole

[0840] A mixture of 2-methyl-2-(4-nitro-phenyl)-propionic acid (5 g, 24mmol) and a few drops DMF in SOCl₂ was stirred at reflux for 16 h. Theresulting solution was concentrated to give corresponding acid chlorideas a brown solid.

[0841] To a mixture of the acid chloride (2.33 g, 10.2 mmol), aceticacid hydrazide (0.91 g, 12.2 mmol), Et₃N (2.86 mL, 20.2 mmol) in CH₂Cl₂(50 mL) was added 2 crystals of DMAP at RT. The resulting mixture wasstirred for 16 h and concentrated. A solution of the residue in 50 mL ofPOCl₃ was heated at 95° C. for 16 h. The resulting mixture wasconcentrated and diluted with ice-H₂O and EtOAc. The organic layer waswashed with saturated aq. NaHCO₃ solution twice, dried over Na₂SO₄, andconcentrated. The residue was purified by SiO₂ chromatography (hexane:EtOAc=1:1) to give the titled compound as a pale yellow crystallinesolid. MS: (ES+) 248 (M+H). Calc'd for C₁₂H₁₄N₃O₃-248.10.

PreparationCXCV-2-Methyl-5-[1-methyl-1-(4-amino-phenyl)-ethyl]-[1,3,4]oxadiazole

[0842] A mixture of2-methyl-5-[1-methyl-1-(4-nitro-phenyl)-ethyl]-[1,3,4]oxadiazole (1.36g, 5.5 mmol) and Pd/C (68 mg) in EtOAc (50 mL) was stirred under 1 atmof H₂ for 16 h. The resulting slurry was filtered over Celite®, and thefiltrate was concentrated to give the titled compound as a pale yellowcrystalline solid. MS: (ES+) 218 (M+H). Calc'd for C₁₂H₁₆N₃O-218.12.

Preparation CXCVI-4-[1-Methyl-1-(4-nitro-phenyl)-ethyl]-pyrimidine

[0843] To a mixture of 1-(4-nitro-phenyl)-propan-2-one (5.32 g, 29.7mmol), triethylbenzylammonium chloride (0.34 g, 1.5 mmol), and 13 mL ofaq. 5N KOH solution (65.3 mmol) in CH₂Cl₂ was added CH₃I (4.06 mL, 65.3mmol). The resulting mixture was stirred at 40° C. then diluted withEtOAc and H₂O. The organic layer was dried and concentrated.

[0844] To the residue (1.0 g, 4.8 mmol) in toluene (30 mL) was addeddimethylformamide dimethylacetal (1.27 mL, 9.6 mmol). The resultingmixture was heated at reflux for 6 h, then concentrated to give1-dimethylamino-4-methyl-4-(4-nitro-phenyl)-pent-1-en-3-one as a yellowsolid. MS: (ES+) 263 (M+H). Calc'd for C₁₄H₁₉N₂O₃-263.13.

[0845] A mixture of1-dimethylamino-4-methyl-4-(4-nitro-phenyl)-pent-1-en-3-one (0.5 g, 1.9mmol), formamidine hydrochloride (0.305 g, 3.8 mmol), and NaOEt (1.29 g,4.0 mmol) was heated in Smith synthesizer under microwave for 10 min at150° C. The resultant was diluted with H₂O and EtOAc. The organic layerwas dried, and the residue was used without further purification. MS:(ES+) 244 (M+H). Calc'd for C₁₃H₁₄N₃O₂-244.10.

Preparation CXCVII-5-[1-Methyl-1-(4-nitro-phenyl)-ethyl]-1H-pyrazole

[0846] A mixture of1-dimethylamino-4-methyl-4-(4-nitro-phenyl)-pent-1-en-3-one (0.36 g, 1.4mmol) and hydrazine hydrate (1.0 g, 6.25 mmol) in EtOH was heated at 50°C. for 3 h. The mixture was concentrated, and the residue was dilutedwith H₂O and EtOAc. The organic layer was dried over Na₂SO₄ andconcentrated to give the titled compound as a yellow solid. MS: (ES+)232 (M+H.) Calc'd for C₁₂H₁₄N₃O₂-232.10.

PreparationCXCVIII-2-Methyl-2-(4-nitro-phenyl)-1-pyrrolidin-yl-propan-1-one

[0847] To a round bottom flask charged with2-methyl-2-(4-nitro-phenyl)-propionic acid, was added 6.5 ml of SOCl₂.The mixture was heated to 80° C., with stirring under inert atmospherefor 3.5 h. The mixture was cooled to RT, and then dried in-vacuo. Theresidue was placed under high vac. After completely dry, the residue wasused without further purification.

[0848] To the residue was added 10 ml of CH₂Cl₂, along with Et₃N and themixture was cooled to 0° C. on an ice/H₂O bath. Pyrrolidine 0.46 mL(1.25 eq.) was added into the mixture, then stirred to RT under inertatmosphere. After 3 h of stirring, the mixture was quenched with H₂O,diluted with CH₂Cl₂, and transferred to a separatory funnel. Theorganics were collected, combined, dried over Na₂SO₄ and filtered. Thecrude was concentrated in vacuo. After drying, the title compound wasproduced as an amorphous solid. MS: 263 (M+1) ; calc'd forC₁₄H₁₈N₂O₃-262

Preparation CXCIX-4-(1,1-Dimethyl-2-pyrrolidin-1-yl-ethyl-phenylamine

[0849] To a 3-neck round bottom flask, charged with2-Methyl-2-(4-nitro-phenyl)-1-pyrrolidin-yl-propan-1-one was added 66 mlof 1M BH₃/THF soln, while the mixture was maintained at 0° C. on anice/H₂O bath. The mixture was stirred under inert atmosphere overnight.A couple drops of 5N NaOH was added slowly to the reaction mixture forquenching. After stirring an additional 5 min, 22 ml of 5N NaOH wasadded into the reaction mixture, then stirred vigorously for 3 h. Themixture was diluted with 50 ml of 1N NaOH and 100 ml of EtOAc, thentransferred into a sep. funnel. The organics were collected andconcentrated in vacuo. The residue was dissolved in CH₂CL₂, then NaHCO₃soln. was added into the mixture the organic extracts were dried overNa₂SO₄, filtered, then concentrated in vacuo.

[0850] To a round bottom flask charged with Pd/C in MeOH under inertatmosphere, was added l-[2-methyl-2-(4-nitro-phenyl)-propyl]-pyrrolidinein MeOH and H₂ was added while stirring vigorously overnight. Themixture was filtered through Celite® and concentrated in vacuo to yielda light yellow oil. MS: 219 (M+1); calc'd for C₁₄H₂₂N₂.

Preparation CC-1-methyl-1-(4-nitro-phenyl)-ethylamine

[0851] To a round bottom flask charged with2-methyl-2-(4-nitro-phenyl)-propionic acid (10 g; 0.0440 mole), wasadded SOCl₂ (32 ml). The mixture was heated to reflux, until completionof the reaction. After heating, the residual SOCl₂ was removed by invacuo, then placed the residue on high vac. The crude was used withoutfurther purification.

[0852] To the residue, was added 20 ml toluene and stirred. Then slowlyNaN₃ (7.14 g; 0.1099 mole) was added into the mixture, and stirredvigorously under inert atmosphere for 1.5 h. The mixture was poured into50 ml H₂O and transferred into a sep. funnel, with 50 ml EtOAc. Theorganics were collected, dried, filtered, and concentrated in-vacuo. Theresidue was dissolved in toluene and heated to 100° C. while stirringvigorously under inert atmosphere for 1 h. The solvent was removedin-vacuo, 20% HCl aq was added and the mixture stirred vigorously underreflux conditions at 100° C. for 9 h. The mixture was evaporatedin-vacuo and to the residue was added 50 ml of 5N NaOH and 80 ml EtOAc,then transferred the mixture to a sep. funnel. The organic layer wascollected, dried, filtered, and conc. in-vacuo. The residue was purifiedon silica-gel column in a solvent gradient of 80% EtOAc/Hexanes to 10%MeOH/CH₂CL₂ yielding a brown solid resulted. MS: 181 (M+1); calc'd forC₉H₁₂N₂O₂-180.

PreparationCCI-[1-(4-Amino-phenyl)-1-methyl-ethyl]-(2-methylsulfanyl-pyrimidin-4-yl)-amine

[0853] To a Personal Chemistry reaction tube, was added1-methyl-1-(4-nitro-phenyl)-ethylamine, along with4-chloro-2-methylsulfanyl-pyrimidine, DIEA (2.0 eq) and t-BuOH (0.6 ml).The tube was heated by microwave to 150° C. for 10 min. After heating,the crude was diluted with CH₂CL₂ and H₂O, then transferred into a sep.funnel. The organics were collected, dried over Na₂SO₄, thenconcentrated in vacuo. The crude was used without further purification.

[0854] To a round bottom flask charged with PtO₂ (12% wt.) in MeOH (5ml), was added crude nitro-intermediate (0.170 g.; 0.0006 mole). Themixture was stirred vigorously under H₂ for 2.5 h. The mixture wasfiltered through Celite® and concentrated in-vacuo. The desired materialwas purified by silica-gel chromatography in a solvent gradient of 80%EtOAc/Hexanes to 5% MeOH/CH₂CL₂. After drying in high vac, the titlecompound resulted as a light yellow amorphous solid.

Preparation CCII-2-(2,2,2-Trifluoro-ethoxy)-isonicotinonitrile

[0855] To the suspension of NaH (2.78 g, 0.11 mole) in THF 100 mL)2,2,2-trifluoroethanol (10 g, 0.1 mol) was added slowly. The mixture wasstirred at RT till it turned clear. A solution of2-chloro-isonicotinonitrile (13.8 g, 0.1 mol) in THF (100 mL) was slowlyadded and stirred at reflux for 3 h. After filtration and concentration,the crude oily compound was purified through column chromatographyproviding pure compound as an oil.

PreparationCCIII-C-[2-(2,2,2-Trifluoro-ethoxy)-pyridin-4-yl]-methylamine hydrogenchloride

[0856] A mixture of 2-(2,2,2-trifluoro-ethoxy)-isonicotinonitrile (3.90g, 19.40 mmol), 12N HCl(8.0 mL) and 10% Pd/C (800 mg) in MeOH (100 ml)was stirred under a balloon of H₂ for 7 h. After filtration, thefiltrate was concentrated to give compound as a white solid. MS (ES+):206.9 (M+H)⁺. Calc'd. for C₈H₉F₃N₂O -206.07.

Preparation CCIV-2-Bromomethyl-3-nitro-benzoic acid methyl ester

[0857] The mixture of methyl 2-methyl-3-nitro benzoate (5.06 g, 25.9mmol), NBS (5.54 g, 31.1 mmol), and AIBN (0.43 g, 2.59 mmol) in 100 mlof anhydrous CCl₄ was heated at reflux under N₂ for 22 h, cooled to RT,diluted with EtOAc, and washed with Na₂CO₃ (aq). The organic portion wasseparated, washed with brine, dried with Na₂SO₄, filtered, andcondensed. The crude material was purified by flash columnchromatography to yield pure product, which was used without furtherpurification.

Preparation CCV-4-Nitro-2, 3-dihydro-isoindol-1-one

[0858] NH₃ (2.0 M in MeOH, 50 ml) was slowly added to the solution of2-bromomethyl-3-nitro-benzoic acid methyl ester (4.46 g, contaminatedwith a small amount of assumed starting material, 16.3 mmol) in 30 ml ofMeOH at RT. The resulting mixture was stirred at RT overnight, toprovide the title compound as a white solid. MS (ES⁺): 179.2 (M+H)⁺.Calc'd for C₈H₆N₂O₃-178.14.

Preparation CCVI-4-Amino-2, 3-dihydro-isoindol-1-one

[0859] To the suspension of 4-nitro-2,3-dihydro-isoindol-1-one (2.40 g,13.5 mmol) in 100 ml of MeOH was added Pd/C (10 wt %, 0.36 g). Themixture was then placed under H₂ from a balloon, stirred at RT for 24 h,filtered through Celite®, and condensed to give the titled compound as alight greenish solid. MS (ES⁺): 149.1 (M+H)⁺. Calc'd for C₈H₈N₂O-148.16.

Preparation CCVII-Pyridin-4-ylmethyl-carbamic acid tert-butyl ester

[0860] Boc anhydride (23 g, 105 mmol) was carefully added to a solutionof pyridin-4-yl-methylamine (11 g, 102 mmol) and DMAP (0.5 g, 4 mmole)in CH₂CL₂ (150 mL). The reaction was extended for 1 hr after theaddition. The reaction mixture was concentrated in vacuo and the residuewas recrystallized in EtOAc to afford an off white crystal as thedesired compound.

Preparation CCVIII-(1-Oxy-pyridin-4-ylmethyl)-carbamic acid tert-butylester

[0861] Pyridin-4-ylmethyl-carbamic acid tert-butyl ester (2.1 g, 10mmol) was dissolved in a one to one mixture of aqueous MeOH (200 mL)with NaHCO₃ (5 g, 60 mmol) and Oxone® (12.3 g, 20 mmol). The mixture wasstirred overnight then concentrated in vacuo to remove MeOH. Theresulted aqueous mixture was diluted with H₂O (150 mL) and filtered. Thefilter cake was washed with H₂O and dried to afford a white solid as thedesired compound.

Preparation CCIX-C-(1-Oxy-pyridin-4-yl)-methylamine

[0862] Oxy-pyridin-4-ylmethyl)-carbamic acid tert-butyl ester (2.1 g,9.4 mmol) was dissolved in a 4N HCl in dioxane solution (50 mL) andheated to 50° C. for 2 h. After removing solvent in vacuo, a white solidwas received as an HCR salt of the desired compound.

Preparation CCX-2-(4-Methoxy-benzylamino)-isonicotinonitrile

[0863] To pyridine (500 mL) were added 2-chloroisonicotinonitrile (22.0g, 159 mmole), para-methoxybenzylamine (25 g, 114% Meq.), and NaHCO₃ (30g). The mixture was heated under reflux overnight. After cooling to RT,the mixture was filtered and the filter cake was rinsed with CH₂Cl₂. Thecombined filtrate was concentrated to dryness in vacuum to form a yellowsolid. This solid is then recrystalized in EtOAc to give a light yellowcrystalline compound and the mother liquor was concentrated andsubjected to EtOAc again (repeating three times) to yield the desiredcompound.

Preparation CCXI-(4-Aminomethyl-pyridin-2-yl)-(4-methoxy-benzyl)-amine

[0864] 2-(4-Methoxy-benzylamino)-isonicotinonitrile (12 g, 50 mmole) wasdissolved in a mixed solvent of EtOH (800 mL) Et₃N (200 mL) andsuspended with 2 g of Pd/C (10%). After removing air with vacuum, theflask was charged with H₂ with a balloon. The H₂ balloon was refilledevery morning and evening. Pd/C was recharged twice (1.3 g each) on days2 and 3. Reaction was completed on the 4^(th) day and the reactionmixture was filtered through a pad of Celite®. The filter cake wasrinsed with MeOH and the combined filtrate was concentrated in vacuo togive the desired compound as a light brown solid.

Preparation CCXII-4-Aminomethyl-pyridin-2-ylamine

[0865] (4-Aminomethyl-pyridin-2-yl)-(4-methoxy-benzyl)-amine (12 g, 50mmole) was dissolved in TFA (150 mL) and heated to reflux for 1 h. Aftercooling, the reaction mixture was concentrated in vacuum and the residuewas partitioned between HCl (1N, aq.) and EtOAc. The aqueous layer waswashed with EtOAc then hexanes and concentrated to dryness in vacuum togive an off white solid as a dihydrochloric salt.

Preparation CCXIII-2-Methylamino-isonicotinonitrile

[0866] To a solution of 2-chloroisonicotinonitrile (22.0 g, 159 mmole)in pyridine (500 mL) was added methylamine in THF (2N, 160 mL), andNaHCO₃ (54 g). The mixture was heated to 120° C. in a sealed vessel for40 h. After cooled to RT, the mixture was filtered and the filter cakewas washed with CH₂Cl₂. The combined filtrated was concentrated in vacuoto give a yellow solid (21 g) as the desired compound.

Preparation CCXIV-(4-Aminomethyl-pyridin-2-yl)-methyl-amine

[0867] A suspension of 2-Methylamino-isonicotinonitrile (5.6 g) and Pd/C(10%, 4 g) in EtOH (150 mL) and TEA (40 mL) was placed in a 500 mL ParrHydrogenation bottle and hydrogenated under 60 psi of H₂ over night.After filtering through a pad of Celite®, the reaction mixture wasconcentrated in vacuo to give a yellow oil as the desired compound.

Preparation CCXV-3-Fluoro-pyridine 1-oxide

[0868] 3-Chloroperoxybenzoic acid (70%, 35.0 g, 142 mmol) was added tothe solution of 3-fluoropyridine (6.90 g, 71.1 mmol) in 200 ml ofCH₂Cl₂, the mixture was stirred at RT overnight, washed with a smallamount of saturated NaHCO₃ solution, dried with Na₂SO₄, filtered,condensed, the crude compound was purified by flash columnchromatography (1 to 2% of MeOH in CH₂Cl₂), the titled compound wasobtained as a light yellowish solid. MS (ES⁺): 114.1 (M+H)⁺. Calc'd forC₅H₄FNO-113.09.

Preparation CCXVI-3-Fluoro-pyridine-2-carbonitrile

[0869] The mixture of 3-fluoro-pyridine 1-oxide (0.99 g, 8.75 mmol),trimethylsilyl cyanide (4.80 ml, 35.0 mmol), and triethyl amine (1.84ml, 13.2 mmol) in 100 ml of CH₃CN was heated at reflux overnight. Thesolvents were removed, under reduced pressure and the residue waspartitioned between EtOAc and saturated NaHCO₃. The organic portion wasseparated, dried with Na₂SO₄, filtered, condensed, the crude compound aspurified by flash column chromatography (10 to 20% of EtOAc in hexanes).The titled compound was obtained as a light yellowish solid. MS (ES⁺):123.1 (M+H)⁺. Calc'd for C₆H₃FN₂-122.10.

Preparation CCXVII-C-(3-Fluoro-pyridin-2-yl)-methylamine

[0870] The mixture of 3-fluoro-pyridine-2-carbonitrile (0.81 g, 6.63mmol) and Pd/C (0.20 g, 10% wt)in 10 ml of MeOH and 2.7 ml ofconcentrated HCl was placed under H₂ which was provided by a balloon andstirred at RT for 4 h, filtered through Celite®, condensed, the residuewas purified by flash column chromatography, 0.13 g of the titledcompound was obtained as a light yellowish oil. MS(ES⁺): 127.1 (M+H)⁺.Calc'd for C₆H₇FN₂-126.13.

Preparation CCXVIII: 5-Bromo-pyridine-2-carbonitrile

[0871] The mixture of 2,5-dibromopyridine (4.74 g, 20.0 mmol), zinccyanide (1.40 g, 12.0 mmol), zinc dust (0.059 g, 0.90 mmol), andPd(dppf)Cl₂.CH₂Cl₂ (0.36 g, 0.44 mmol) in 25 ml of DMF was heated atreflux for 5 h, cooled to RT, diluted with H₂O, extracted with EtOAc,the organic portion was washed with brine, the solvents were removed,the crude compound was purified by flash column chromatography (5 to 15%of EtOAc in hexanes), the titled compound was obtained as an off-whitesolid.

Preparation CCXIX-5-Fluoro-pyridine-2-carbonitrile

[0872] The mixture of 5-bromo-pyridine-2-carbonitrile (0.50 g, 2.73mmol), and KF (0.48 g, 8.20 mmol) in 10 ml of 1-methyl-2-pyrrolidinonewas stirred at 175° C. for 18 h, cooled to RT, diluted with H₂O,extracted with EtOAc, the combined organic portions were washed withH₂O, brine, dried with Na₂SO₄, filtered, condensed, the crude compoundwas purified by flash column chromatography (5 to 20% of EtOAc inhexanes). The titled compound was obtained as an off-white solid.

Preparation CCXX-C-(5-Fluoro-pyridin-2-yl)-methylamine

[0873] The mixture of 5-fluoro-pyridine-2-carbonitrile (0.16 g, 1.27mmol) and Pd/C (0.030 g, 10% wt) in 15 ml of MeOH and 0.50 ml ofconcentrated HCl was placed under H₂ which was provided by a balloon andstirred at RT for 4 h, filtered through Celite®, condensed, the residuewas purified by flash column chromatography. The titled compound wasobtained as a light yellowish solid. MS(ES⁺): 127.2 (free base)(M+H)⁺.Calc'd for C₆H₇FN₂ (free base)-126.13.

Preparation CCXXI-1H-Pyrrolo[2,3-b]pyridine 7-oxide

[0874] To a suspension of 1H-pyrrolo[2,3-b]pyridine (10.0 g) and NaHCO₃(45.2 g) in 1:1 MeOH/H₂O (1000 mL) was added Oxone® (106 g) in potionsduring 40 min period. The mixture was stirred at RT for 5 h. The soldwas removed by filtration and the filtrate was concentrated to 200 mL involume. This aqueous phase was extracted with CH₂Cl₂ (200 mL×7) toafford 1H-pyrrolo[2,3-b]pyridine 7-oxide.

Preparation CCXXII-4-chloro-1H-pyrrolo[2,3-b]pyridine

[0875] To a cooled POCl₃ (50 mL) in a dried round bottom flask,1H-pyrrolo[2,3-b]pyridine 7-oxide (5.73 g, step A) was added in potions.The mixture was heated to reflux for 5 h. After cooled down to RT, POCl₃was evaporated under high vacuum under gentle heating (40-50° C.) toobtain black residue. 50 mL of H₂O was added slowly and pH was adjustedto 8-9 with Na₂CO₃ (first with solid, then saturated aqueous solution).The resulting priticipate was collected by filtration, washed with coldH₂O and dried in a vacuum oven (50° C.) to give4-chloro-1H-pyrrolo[2,3-b]pyridine as tan powder.

Preparation CCXXIII-1-(4-iodo-pyrrolo[2,3-b]pyridin-1-yl)-ethanone

[0876] To a suspension of 4-chloro-1H-pyrrolo[2,3-b]pyridine (3.80 g,step B) and NaI (19.15 g) in CH₃CN (40 mL) was added acetyl chloride(5.0 mL) slowly. The mixture was heated to reflux for overnight. Aftercooled to RT, 40 mL of 10% Na₂CO₃ and 40 mL of 10% NaHSO₃ were added.After stirring for 15 min, the mixture was extracted with EtOAc 4 times.The combined organic phases were washed with brine, dried over MgSO₄ andconcentrated to give a brown residue as the crude compound, which waspurified by chromatography through silica gel (220 g, 5 to 15%EtOAc/hexanes to afford 1-(4-iodo-pyrrolo[2,3-b]pyridin-1-yl)-ethanoneas white solid.

Preparation CCXXIV-1-acetyl-1H-pyrrolo[2,3-b]pyridine-4-carbonitrile

[0877] A mixture of 1-(4-iodo-pyrrolo[2,3-b]pyridin-1-yl)-ethanone (4.30g, step C), CuCN (6.841 g), Pd₂dba₃ (0.729 g), and dppf (1.636 g) in 85mL of dioxane was heated to reflux for 2 h. Solid was removed byfiltration through a pad of Celite®. The filtrate was concentrated togive a yellow solid as crude compound, which was purified bychromatography through silica gel (250 g, 5-30% EtOAc/hexanes, stepwisegradient) to afford 1-acetyl-1H-pyrrolo[2,3-b]pyridine-4-carbonitrile asa white fluffy solid.

Preparation CCXXV-1-(4-aminamethyl-pyrrolo[2,3-b]pyridin-1-yl)-ethanone

[0878] A mixture of 1-acetyl-1H-pyrrolo[2,3-b]pyridine-4-carbonitrile(0.872 g, step D), 10% Pd/C (0.882 g), 20 mL of Et₃N, and 80 mL of EtOHwas stirred at RT under balloon pressure of H₂ for overnight. Solid wasremoved by filtration through a pad of Celitee and the filtrate wasconcentrated to yield a cream color residue, which was purified bychromatography through silica gel (70 g, 2 to 5% MeOH/CHCl₃ with 1%NH₄OH) to afford 1-(4-aminomethyl-pyrrolo[2,3-b]pyridin-1-yl)-ethanoneas a white solid.

PreparationCCXXVI-N-(1-acetyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-ylmethyl)-acetamide

[0879] To a mixture of 1-acetyl-1H-pyrrolo[2,3-b]pyridine-4-carbonitrile(0.691 g, example 15, step D), 10% Pd/C (0.702 g), 5 mL of Et₃N, and 20mL of EtOAc was added acetic anhydride (1.0 mL). The mixture was stirredat RT under balloon pressure of H₂ for overnight. Solid was removed byfiltration through a pad of Celite® and the filtrate was concentrated toyield a white residue, which was purified by chromatography throughsilica gel (150 g, 1 to 5% MeOH/CHCl₃ with 1% NH₄OH, stepwise gradient)to affordN-(1-acetyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-ylmethyl)-acetamide(0.50 g) as white solid.

PreparationCCXXVII-C-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-methylaminehydrogen chloride salt

[0880] A mixture ofN-(1-acetyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-ylmethyl)-acetamide(0.50 g, step A), HCl (conc., 3 mL) and EtOH (12 mL) was heated to 70°C. for overnight. Additional 3 mL of conc. HCl was added to the reactionand the heating was continued for 3 more days. Solvent was evaporated togive a white residue as crudeC-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-methylamine HCl salt,which was used without further purification.

General Procedure for the Preparation of 2-amino-4-methylaminopyridinesPreparation CCXXVIII-2-aminoisonicotinonitrile

[0881] To a slurry of 2-chloro-4-cyanopyridine (10.00 g, 0.079 mol) andsodiumbicarbonate (19.92 g, 0.237 mol) in amine (0.174 mol) was addedpyridine (35.0 mL) and the reaction was heated to 90° C. for 3 h. Thereaction was then cooled to RT, diluted with the addition of CH₂Cl₂ (100mL) and filtered. The solid was washed with EtOAc. Combined washes wereconcentrated in vacuo. A mixture of MeOH/hexanes was added and kept inthe fridge for 12 h. The crystals that formed were filtered and washedwith hexanes.

Preparation CCXXIX-2-amino-4-methylaminopyridine

[0882] To a mixture of 2-aminoisonicotinonitrile (0.043 mol) and Pd/C(10%, 6.00 g) was added Et₃N (40.0 mL) and EtOH (160.0 mL)in a parrbottle and hydrogenated at 50 psi for 12 h. Crude mixture was filteredthrough Celite®, concentrated under vacuo and dried under high vacuum toyield compound.

Preparation CCXXX-(2-Pyrrolidin-1-yl-pyridin-4-yl)-methylamine

[0883] Prepared according to the general procedure with pyrrolidine asthe amine.

Preparation CCXXXI-(2-Morpholin-4-yl-pyridin-4-yl)-methylamine

[0884] Prepared according to the general procedure with morpholine asthe amine.

PreparationCCXXXII-3,9,9-Trimethyl-6-nitro-4,9-dihydro-3H-3-aza-fluorene

[0885]4-[1-(2-Bromo-4-nitro-phenyl)-1-methyl-ethyl]-1-methyl-1,2,3,6-tetrahydro-pyridine(9 g), Pd(OAc)₂ (900 mg), and DIEA (15 mL) was dissolved in DMF (300mL), and heated to 80° C. overnight. Solvents were removed in vacuo. Theresidue was partitioned between CH₂Cl₂/NaHCO₃(sat, aq.). The CH₂Cl₂layer was washed with brine, dried over Na₂SO₄ and concentrated invacuo. The residue was purified via flash chromatography on silica togive the desired compound. (MS: M+H=257)

PreparationCCXXXIII-3,9,9-Trimethyl-2,3,4,4a,9,9a-hexahydro-1H-3-aza-fluoren-6-ylamine(156)

[0886] 3,9,9-Trimethyl-6-nitro-4,9-dihydro-3H-3-aza-fluorene (700 mg)was dissolved in EtOH (20 mL) with aqueous HCl (1N, 5 mL) and suspendedwith Pd/C (10%, 100 mg). The flask was capped with a balloon filled withH₂. The reaction was completed in 6 h at RT. The reaction mixture wasfiltered through a layer of Celite® with MeOH. The combined filtrate wasconcentrated to give desired compound. (MS: M+H=231).

Preparation CCXXXIV-2-Chloro-5-nitro-phenol

[0887] A mixture of 2-chloro-4-nitroanisole (10 g, 53.3 mmol) andpyridinium chloride (50 g, 426 mmol) was heated at 200° C. for 3 h.After cooling to RT, the mixture was dissolved in 150 mL of aqueous 2NHCl and 150 mL of EtOAc. The organic phase was separated and was washedwith aqueous 2N HCl (2×100 mL). The resulting organic phase was driedover MgSO₄ and concentrated in vacuo. The title compound was obtainedvia chromatography (silica gel, 10:1 hexane/EtOAc) as a yellow solid.

PreparationCCXXXV-3-(2-Chloro-5-nitro-phenoxymethyl)-azetidine-1-carboxylic acidtert-butyl ester

[0888] To the mixture of 2-chloro-5-nitro-phenol (1.31 g, 7.54 mmol) andK₂CO₃ (1.57 g, 11.31 mmol) in 20 mL of DMF was added3-methanesulfonyloxymethyl-azetidine-1-carboxylic acid tert-butyl ester(2.0 g, 7.54 mol). The reaction mixture was stirred at 50° C. for 1 h.After cooling to room temperature, the reaction mixture was diluted in100 mL of EtOAc and quenched with 50 mL of water. The organic layer wasseparated and the aqueous layer was extracted with EtOAc (2×50 mL). Thecombined organic phases were washed with brine, dried over MgSO₄ andconcentrated in vacuum. The title compound was obtained via columnchromatography (silica gel, 1;1 hexane/EtOAc) as yellow oil with 93%yield.

PreparationCCXXXVI-3-(5-Amino-2-chloro-phenoxymethyl)-azetidine-1-carboxylic acidtert-butyl ester

[0889] To a solution of3-(2-chloro-5-nitro-phenoxymethyl)-azetidine-1-carboxylic acidtert-butyl ester (2.5 g, 7.29 mmol) in 60 mL of MeOH/H₂O (1:1) and 3 mLof acetic acid (J. T. Baker) was added Zn powder (2.3 g, 36.47 mmol,Aldrich) at 0° C. The reaction mixture was stirred at 0° C. for 2 h thenstirred at 10° C. for 2 h. The resulting mixture was filtered through aCelite® pad and the filtrate was concentrated in vacuo. The residue wastreated with 60 mL of saturated aqueous NaHCO₃ and extracted with EtOAc(3×50 mL). The combined organic layers were washed with brine and driedwith MgSO₄. The resulting solution was concentrated in vacuo and thetitle compound was obtained by column chromatography (silica gel, EtOAc)as a yellow solid.

Preparation CCXXXVII:3-(Benzotriazol-1-yloxy)-6-chloro-pyridazine-4-carboxylic acid(4-tert-butyl-phenyl)-amide

[0890] A mixture of 3,6-dichloropyridazine-4-carboxylic acid (1.00 g,5.18 mmol), 4-tert-butylaniline (0.92 ml, 5.60 mmol), TBTU (1.75 g, 5.44mmol), and DIEA (1.80 ml, 10.4 mmol) in 7.5 ml of anhydrous DMF wasstirred at RT under N₂ overnight. The mixtrue was diluted with H₂O,extracted with EtOAc, and the combined organic portions were washed withbrine, dried with Na₂SO₄, filtered, and condensed. The crude compoundwas purified by flash column chromatography (hexanes/EtOAc/CH₂Cl₂, 9:0:1to 7:2:1), to provide the desired compound as a light yellowish solid.MS (ES⁺): 423.0 (M+H)⁺. Calc'd for C₂₁H₁₉ClN₆O₂-422.87.

Preparation CCXXXVIII-3-Hydroxymethyl-azetidine-1-carboxylic acid benzylester

[0891] To a mixture of azetidine-1,3-dicarboxylic acid monobenzyl ester(6.4 g) in THF (200 mL) was added BH₃.THF (6 eq, 163 mL, 1M solution)dropwise via an addition funnel at −40° C. under an N₂ atmosphere. Thesolution was warmed to RT and stirred overnight. To the reaction, 5NNaOH (50 mL) was added and then concentrated under vacuum. The resultingaqueous solution was extracted with Et₂O (3×100 mL). The organic layerwas dried over Na₂SO₄ and evaporated to give the title compound whichwas used without further purification.

Preparation CCXXXIX -3-Methanesulfonyloxymethyl-azetidine-1-carboxylicacid benzyl ester

[0892] 3-Hydroxymethyl-azetidine-1,3-dicarboxylic acid monobenzyl ester(6.6 g) was dissolved in CH₂Cl₂ (100 mL) and brought to −15° C. Whilestirring, TEA was added (3 eq, 9.43 g) followed by methanesulphonicchloride (2.0 eq, 7.69 g) and allowed to come to RT and stirred for 1 h.The resulting organic solution was extracted with water (3×100 mL). Theorganic layer was dried over Na₂SO₄ and evaporated to give the desiredproduct as a clear oil which was used without further purification.

Preparation CCXL-3-Nitro-5-trifluoromethyl-phenol

[0893] A flask containing 1-Methoxy-3-nitro-5-trifluoromethyl-benzene(10 g) and hydrochloride pyridine (10 eq, 52.0 g) was heated to 210 C.and stirred for 12 h. Once complete, the reaction was cooled and theresidue was dissolved in CH₂Cl₂ and washed twice with water (100 mL).The organic layer was concentrated under vacuum and then set in thefreezer overnight. The resulting crystalline product was filtered offand washed with ether and used as is.

PreparationCCXLI-3-(3-Nitro-5-trifluoromethyl-phenoxymethyl)-azetidine-1-carboxylicacid benzyl ester

[0894] A mixture of 3-nitro-5-trifluoromethyl-phenol (750 mg, Step C),K₂CO₃ (3 eq., 1.5 g) and 3-hydroxymethyl-azetidine-1-carboxylic acidbenzyl ester (1.1 eq., 1.2 g) in DMF was heated to 80° C. for 1 h. Thesolution was cooled to RT then filtered and concentraced under vacuum.The residue was dissolved in CH₂Cl₂ and washed with H₂O twice, followedby brine. The organic layer was dried over Na₂SO₄ and evaporated underreduced pressure. The residue was purified by column chromatographyusing 5% MeOH/CH₂Cl₂ to provide the desired compound as a colorlesssolid.

PreparationCCXLII-3-(3-amino-5-trifluoromethyl-phenoxymethyl)-azetidine-1-carboxylicacid benzyl ester

[0895] To a solution of 3-(3-nitro-5-trifluoromethyl-mg) and NH₄Cl (1.1eq., 80 mg) was added iron dust (3 eq., 220 mg) in a 10% water/EtOHsolution. The solution was heated to reflux for 6 h. The solution wascooled, then filtered through a pad of Celite®. The resulting solutionwas concentrated under vacuum to provide the desired compound as a darkyellow solid and used as is.

Preparation CCXLIII-3-nitro-5-(trifluoromethyl)phenylamine

[0896] To a solution of 3,5-dinitrobenzotrifluoride (10 g, 42 mmols, 1eq.) in 150 mL of EtOH was added 17.6 mL (258.3 mmols, 6.15 eq.) ofammonium sulfide in water (50% by weight, Aldrich). The reaction washeated to reflux for 16 h during which time it became orange and ayellow precipitate formed. After cooling the volume was reduced toapproximately 50 mL. The solid was removed by filtration and thefiltrate evaporated to dryness in vacuo. The resulting orange solid waspurified by column chromatography eluting with a step gradient of 20-30%EtOAc:hexane to provide the compound as a yellow/orange solid.

PreparationCCXLIV-N-(3-nitro-5-(trifluoromethyl)phenyl)methanesulfonamide

[0897] 3-Nitro-5-(trifluoromethyl)phenylamine (2 g, 9.7 mmols, 1 eq) wasdissolved in 100 mL of CH₂Cl₂. The yellow solution was cooled to 0° C.Et₃N (2 mL, 14.55 mmols, 1.5 eq) was added followed by mesyl chloride(0.75 mL, 9.7 mmols, 1 eq). The reaction was stirred for 2 h at 0° C.and warmed to RT. Pyridine (0.785 mL, 9.7 mmols, 1 eq) and a catalyticamount of dimethylamine pyridine were added. The reaction was stirred atRT for 16 h. An additional equivalent of mesyl chloride was added andthe reaction was heated to reflux for 24 h. After cooling, the solventwas removed in vacuo, and the residue redissolved in CH₂Cl₂. Thesolution was washed twice with 2 N HCl and once with brine. After dryingover Na₂SO₄, the solution was filtered and the solvent removed. Theresulting solid was triturated briefly with 10% EtOAc:hexane to providea white solid that was a mixture of sulfonimide and sulfonimide.

[0898] The above mixture was dissolve in 20 mL of MeOH that had beensaturated with K₂CO₃. After 30 min the reaction was stripped and theresulting solid portioned between 2 N HCl and CH₂Cl₂. The CH2Cl2 wasdryed over Na₂SO₄ and stripped to provide and off-white solid.

Preparation CCXLV-(3S)-tetrahydro-3-furanyl3-nitro-5-(trifluoromethyl)phenylcarbamate

[0899] 3-(S)-Hydroxytetrahydrofuran (4.8 mL, 60.7 mmols, 5 eq) wasdissolved in 60 mL of toluene. The solution was cooled to 0° C. and Et₃N(5.1 mL, 36.4 mmols, 3 eq) was added. Trichloromethyl chloroformate(3.65 mL, 30.33 mmols, 2.5 eq) was added slowly. The solurion wasstirred at 0° C. for 45 min. 3-Amino-5-ntrobenzotrifluoride (2.5 g,12.13 mmols, 1 eq) was added dropwise in 20 mL of toluene. The reactionwas stirred at 0° C. for 1 h. An additional 5 eq of3-(S)-hydroxytetrahydrofuran was converted to the chloroformate asdescribed above, and added to the reaction mixture. After an additionalh at 0° C., the reaction was heated to 60° C. for 1 h. The reaction wascooled to RT and concentrated. The residue was dissolved in EtOAc,washed twice with saturated NH₄Cl and once with brine. After being driedover Na₂SO₄ the solution was filtered and the solvent removed in vacuo.The crude product was purified using a Biotage chromatography systemeluting with a gradient of 5% to 35% EtOAc:hexane to yield the desiredcompound.

PreparationCCXLVI-N-(2-((3-nitro-5-(trifluoromethyl)phenyl)oxy)ethyl)-methanesulfonamide

[0900] 2-((3-Nitro-5-(trifluoromethyl)phenyl)oxy)ethylamine (4.05 g,16.2 mmols, 1 eq) was dissolved in 100 mL of CH₂Cl₂. The solution wascooled to 0° C. Pyridine (2.6 mL, 32.4 mmols, 2 eq) was added followedby mesyl chloride (1.25 mL, 16.2 mmols, 1 eq). The reaction was stirredfor 18 h during which time it was warmed slowly to RT. The solvent wasremoved in vacuo, and the residue dissolved in EtOAc. The resultingsolution was washed twice with 2 N HCl, once with water, and 3× withbrine. After being dried over Na₂SO₄ the solution was filtered andconcentrated. The crude was purified by silica gel chromatographyeluting with 50% to 60% EtOAc:hexane to yield the desired compound.

PreparationCCXLVII-N-(2-((3-amino-5-(trifluoromethyl)phenyl)oxy)ethyl)methanesulfonamide

[0901]N-(2-((3-Nitro-5-(trifluoromethyl)phenyl)oxy)ethyl)-methanesulfonamide(1.7 g, 5.2 mmols, 1 eq) was dissolved in 50 L of MeOH. 10% Pd/C (170mg, 10 weight %) was added and the reaction sparged with H₂. Thesuspension was stirred for 5 h, then filtered trough Celite. Thefiltrate was stripped to yield the title compound.

[0902] The following compounds were prepared similarly to the procedureoutlined above:

[0903] a)3-((((2R)-1-acetyl-2-pyrrolidinyl)methyl)oxy)-5-(trifluoromethyl)phenylamine.

[0904] b) (3S)-tetrahydro-3-furanyl3-amino-5-(trifluoromethyl)phenylcarbamate.

[0905] c) N-(3-amino-5-(trifluoromethyl)phenyl)-methanesulfonamide

PreparationCCXLVIII-(2R)-1-acetyl-2-(((3-nitro-5-(trifluoromethyl)phenyl)oxy)methyl)pyrrolidine

[0906](2R)-2-(((3-nitro-5-(trifluoromethyl)phenyl)oxy)methyl)pyrrolidine (3.46g, 11.9 mmols, 1 eq) was dissolved in 100 mL of CH₂Cl₂. Et₃N (5 mL, 35.7mmols, 3 eq) was added followed by Ac₂O (1.2 mL, 13.1 mmols, 1.1 eq).The reaction was stirred at RT for 1.5 h. The solvent was removed invacuo and the residue disolved in EtOAc. The solution was washed onceeach with saturated NH₄Cl, 1 N HCl, and twice with brine. The organiclayer was dried over Na₂SO₄ filtered and concentrated in vacuo. Thecrude material was purified on a Biotage chromatography system elutingwith a gradient of 10% to 75% EtOAc:hexane to yield the title compound.

EXAMPLE 1

[0907]

N-(4-Chlorophenyl){3-[benzylamino](2-pyridyl)}carboxamide

[0908] Step A-Preparation of(3-amino-(2-pyridyl))-N-(4-chlorophenyl)carboxamide

[0909] To a mixture of 3-aminopicolinic acid (552 mg, 4.0 mmol, 1.0 eq)and 4-chloroaniline (1.02 g, 8.0 mmol, 2.0 eq) in CH₂Cl₂ was added EDC(1.2 eq), HOBt (0.5 eq) and TEA (1.2 eq). The reaction was stirred at RTovernight, diluted with CH₂Cl₂, washed with NH₄Cl, dried over Na₂SO₄,filtered and concentrated in vacuo, purified by flash chromatography (4%MeOH/CH₂Cl₂) to give the amide as an white solid. MS (ES+) 248 (M+H)⁺;(ES−): 246 (M−H)⁻.

[0910] Step B-Preparation ofN-(4-chlorophenyl){3-[(4-phenylmethyl)amino](2-pyridyl)}carboxamide

[0911] To a mixture of the amide from Step A (1.0 eq.) and4-benzaldehyde (1.0 eq.) in CH₂Cl₂ was added NaBH(OAc)₃ (1.5 eq). Theresulted mixture was stirred for 2 days at RT, diluted with CH₂Cl₂,washed with saturated NH₄Cl solution, dried over Na₂SO₄, filtered andconcentrated. The crude material was purified through flashchromatography (4% MeOH/CH₂Cl₂) to give the title compound as an whitesolid. MS (ES+): 338 (M+H)⁺; (ES⁻): 336 (M−H)⁻. Calc'd forC₁₉H₁₆ClN₃-337.81.

[0912] The following compounds (Examples 2-4) were analogouslysynthesized by the method described in Example 1.

EXAMPLE 2

[0913]

N-(4-Chlorophenyl)(3-{[(4-nitrophenyl)methyl]amino}(2-pyridyl))-carboxamide

[0914] MS (ES+): 383 (M+H)⁺; (ES⁻): 381 (M−H)⁻. Calc'd forC₁₉H₁₅ClN₄O₃-382.81.

EXAMPLE 3

[0915]

(2-[[(4-methoxyphenyl)methyl]amino](2-pyridyl))-N-(3-fluoro-4-methylphenyl)carboxamide

[0916] MS (ES+): 366 (M+H)⁺. Calc'd for C₂₁H₂₀FN₃O₂-365.41.

EXAMPLE 4

[0917]

(6-Chloro-2-[[(4-methoxyphenyl)methyl]amino[(3-pyridyl))-N-(3-fluoro-4-methylphenyl)carboxamide

[0918] Step A-Preparation of6-chloro-2-[[(4-methoxyphenyl)methyl]amino]pyridine-3-carboxylic acid

[0919] A mixture of 2,6-dichloronicotinic acid (1 g, 5.5 mmol) and4-methoxybenzylamine (1 ml, 7.7 mmol) in a sealed tube was heated at150° C. for 3 h and 120° C. for 16 h. The resulting solution was cooledto RT and CH₂Cl₂ (10 ml) was added. A precipitate which formed wasfiltered and washed with CH₂Cl₂ (20 ml) The filtrate was concentrated,dissolved in EtOAc (30 ml), and extracted with NaOH (2N, 3×15 ml). Thecombined aqueous solution was acidified with HCl (1N) to pH 7, andextracted with CH₂Cl₂ (3×20 ml). The combined extracts were dried andconcentrated. The compound was purified on SiO₂ column (eluted with asolution of hexane-EtOAc 2:1) to give a yellowish solid.

[0920] Step B-Preparation of(6-chloro-2-[[(4-methoxyphenyl)methyl]amino](3-pyridyl))-N-(3-fluoro-4-methylphenyl)carboxamide

[0921] A mixture of6-chloro-2-[[(4-methoxyphenyl)methyl]-amino]pyridine-3-carboxylic acidfrom Step A (100 mg, 0.34 mmol), EDC (107 mg, 0.56 mmol), HOBt (51 mg,0.37 mmol) and DIEA (0.1 ml) in CH₂Cl₂ (10 ml) was stirred at RT underN₂ atmosphere for 16 h. It was taken up in CH₂Cl₂ and washed with H₂Othen aqueous NaHCO₃. The CH₂Cl₂ was evaporated and the oil was placed ona silica gel GF prep plate and eluted with a solution of hexane-EtOAc(4:1). M+H 400.2, M−H 398.1. Calc'd for C₂₁H₁₉ClFN₃O₂: 399.1.

EXAMPLE 5

[0922]

(6-Chloro-2-[[(4-methoxyphenyl)methyl]amino[(3-pyridyl))-N-(3-fluoro-4-methylphenyl)carboxamidehydrochloride

[0923](6-Chloro-2-[[(4-methoxyphenyl)methyl]amino[(3-pyridyl))-N-(3-fluoro-4-methylphenyl)carboxamide(Example 4) was dissolved in MeOH (0.5 ml) and added to a solution ofHCl-Et₂O. The precipitate was collected and washed with Et₂O to givelight yellow solid. MS (ES+): 400.2 (M+H); (ES⁻): 398 (M−H). Calc'd forC₂₁H₁₉ClFN₃O₂-399.851.

EXAMPLE 6

[0924]

(6-Chloro-2-{[(4-methoxyphenyl)methyl]amino}(3-pyridyl))-N-(4-chlorophenyl)carboxamide

[0925] The title compound was analogously synthesized by methoddescribed in Example 4. MS (ES+): 403 (M+H); (ES⁻): 401 (M−H). Calc'dfor C₂₀H₁₇Cl₂N₃O₂-402.28.

EXAMPLE 7

[0926]

2-(3-Fluoro-benzylamino)-N-(4-phenoxy-phenyl)-nicotinamide

[0927] Step A: Preparation of 2-chloro-N-(4-phenoxy-phenyl)-nicotinamide

[0928] 2-Chloropyridine-3-carbonyl chloride (9.15 g, 0.052 mol) wasadded to a stirred solution of 4-phenoxyaniline (10.00 g, 0.054 mol) andDIEA (10.00 ml, 0.057 mol) in CH₂Cl₂ (100 ml) at RT. The mixture wasstirred for 48 h before removal of solvent under reduced pressure. Theresulting residue was dissolved in EtOAc and washed several times withsaturated NaHCO₃ aqueous solution and brine, respectively. The organiclayer was dried over Na₂SO₄ and evaporated to dryness. This material wasre-crystallized from EtOAc/Hexane mixtures followed by filtration andrinsing with Et₂O to leave the desired compound as a white solid. MSm/z: 325 (M+1); 323 (M−1)

[0929] Step B:2-(3-Fluoro-benzylamino)-N-(4-phenoxy-phenyl)-nicotinamide

[0930] 2-Chloro-N-(4-phenoxy-phenyl)-nicotinamide (0.025 g, 0.077 mmol)(Step A) and 3-fluorobenzylamine (0.029 g, 2.31 mmol) were combined andheated at 120° C. neat for 18 h. After cooling to RT, the title compoundwas obtained through purification via preparative HPLC as the TFA salt.MS: (ES+) 414 (M+1)⁺; (ES−): 412 (M−1)⁻. Calc'd. for C₂₅H₂₀FN₃O₂-413.15.

[0931] The following compounds (Examples 8-37) were prepared by themethod similar to that described in Example 7.

EXAMPLE 8

[0932]

N-(4-Phenoxy-phenyl)-2-(3-trifluoromethyl-benzylamino)-nicotinamide

[0933] MS: (ES+) 464 (M+1)⁺; (ES−): 462 (M−1)⁻. Calc'd. forC₂₆H₂₀F₃N₃O₂-463.15.

EXAMPLE 9

[0934]

2-(4-Fluorobenzylamino)-N-(4-phenoxy-phenyl)-nicotinamide

[0935] MS: (ES+) 414 (M +1)⁺; (ES−): 412 (M−1)⁻. Calc'd. forC₂₅H₂₀FN₃O₂-413.15.

EXAMPLE 10

[0936]

N-(4-Phenoxy-phenyl)-2-(4-trifluoromethyl-banzylamino)-nicotinamide

[0937] MS: (ES+) 464 (M+1)⁺; (ES−): 462 (M−1)⁻. Calc'd. forC₂₆H₂₀F₃N₃O₂-463.15.

EXAMPLE 11

[0938]

2-(2-Bromo-benzylamino)-N-(4-phenoxy-phenyl)-nicotinamide

[0939] MS: (ES+) 475 (M+1)⁺; (ES−): 473 (M−1)⁻. Calc'd. forC₂₅H₂₀BrN₃O₂-473.07.

EXAMPLE 12

[0940]

N-(4-Phenoxy-phenyl)-2-(4-trifluoromethoxy-benzylamino)-nicotinamide

[0941] MS: (ES+) 480 (M+1)⁺; (ES−): 478 (M−1)⁻. Calc'd. forC₂₆H₂₀F₃N₃O₃-479.15.

EXAMPLE 13

[0942]

2-(2,3-Difluorobenzylamino)-N-(4-phenoxyphenyl)-nicotinamide

[0943] MS: (ES+) 432 (M+1)⁺; (ES−): 430 (M−1)⁻. Calc'd. forC₂₅H₁₉F₂N₃O₂-431.14.

EXAMPLE 14

[0944]

N-(4-Chlorophenyl)(2-{[(4-cyanophenyl)methyl]amino}(3-pyridyl))carboxamide

[0945] MS (ES+): 363 (M+H); (ES−): 361 (M−H). Calc'd. for C₂₀H₁₅ClN₄O-362.81.

EXAMPLE 15

[0946]

N-(4-Chlorophenyl)(2-{[(2-cyanophenyl)methyl]amino}(3-pyridyl))carboxamide

[0947] MS (ES+): 363 (M+H); (ES−): 361 (M−H). Calc'd. forC₂₀H₁₅ClN₄O-362.81.

EXAMPLE 16

[0948]

N-(4-sec-butylphenyl)-2-[(4-fluorobenzyl)amino]nicotinamide

[0949] MS: (ES+) 378.2 (M+H); (ES−) 376.2 (M−H). Calc'd forC₂₃H₂₄FN₃O-377.45.

EXAMPLE 17

[0950]

N-(4-tert-Butylphenyl)-2-[(4-fluorobenzyl)amino]nicotinamide

[0951] MS: (ES+) 378.2 (M+H); (ES−) 376. (M−H). Calc'd forC₂₃H₂₄FN₃O-377.45.

EXAMPLE 18

[0952]

N-(4-Isopropyl-phenyl)-2-(3-methoxy-benzylamino)-nicotinamide

[0953] MS (ES+): 376 (M+H)⁺; (ES−): 374 (M−H)⁻. Calc'dC₂₃H₂₅N₃O₂-375.47.

EXAMPLE 19

[0954]

(2-{[(3-Aminophenyl)methyl]amino}(3-pyridyl))-N-[4-(methylethyl)phenyl]carboxamide

[0955] MS (ES+): 361 (M+H)⁺; (ES−): 359 (M−H)⁻. Calc'd C₂₂H₂₄N₄O-360.46.

EXAMPLE 20

[0956]

(2-{[(4-Fluorophenyl)methyl]amino}(3-pyridyl))-N-[4-(methylethyl)phenyl]carboxamide

[0957] MS (ES+): 364(M+H)⁺; (ES−): 362. Calc'd C₂₂H₂₂FN₃O-363.43.

EXAMPLE 21

[0958]

(2-{[(4-Fluorophenyl)methyl]amino}(3-pyridyl))-N-[3-(trifluoromethyl)phenyl]carboxamide

[0959] MS: (ES+) 390 (M+H); (ES−) 388. (M−H). Calc'd forC₂₀H₁₅F₄N₃O-389.35.

EXAMPLE 22

[0960]

(2-{[(3,4-Dimethoxyphenyl)methyl]amino}(3-pyridyl))-N-[3-(trifluoromethyl)phenyl]carboxamide

[0961] MS: (ES+) 432 (M+H); (ES−) 430. (M−H). Calc'd for C₂₀H₂₀F₃N₃O₃:431.41.

EXAMPLE 23

[0962]

{2-[Benzylamino](3-pyridyl)}-N-[3-(trifluoromethyl) phenyl]-carboxamide

[0963] MS: (ES+) 372 (M+H); (ES−) 370. (M−H). Calc'd for C₂₀H₁₆F₃N₃O:371.36.

EXAMPLE 24

[0964]

(2-{[(3-Chlorophenyl)methyl]amino}(3-pyridyl))-N-[3-(trifluoromethyl)phenyl]carboxamide

[0965] MS: (ES+) 406 (M+H); (ES−) 404. (M−H). Calc'd for C₂₀H₁₅ClF₃N₃O:405.81.

EXAMPLE 25

[0966]

(2-{[(4-Bromophenyl)methyl]amino}(3-pyridyl))-N-[3-(trifluoromethyl)phenyl]carboxamide

[0967] MS: (ES+) 451 (M+H); (ES−)449. (M−H). Calc'd for C₂₀H₁₅BrF₃N₃O:450.26.

EXAMPLE 26

[0968]

(2-{[(4-Chlorophenyl)methyl]amino}(3-pyridyl))-N-[3-(trifluoromethyl)phenyl]carboxamide

[0969] MS: (ES+) 406 (M+H); (ES−) 404. (M−H). Calc'd for C₂₀H₁₅ClF₃N₃O:405.81.

EXAMPLE 27

[0970]

(2-{[(2,4-Difluorophenyl)methyl]amino}(3-pyridyl))-N-[3-(trifluoromethyl)phenyl]carboxamide

[0971] MS: (ES+) 408 (M+H); (ES−) 406. (M−H). Calc'd for C₂₀H₁₇F₅N₃O:407.34.

EXAMPLE 28

[0972]

2-[1-(4-Fluoro-phenyl)-ethylamino]-N-(3-trifluoromethyl-phenyl)-nicotinamide

[0973] MS: (ES+) 404 (M+H); (ES−) 402. (M−H). Calc'd for C₂₁H₁₇F₄N₃O:403.37.

EXAMPLE 29

[0974]

(2-{[(3,4-Difluorophenyl)methyl]amino}(3-pyridyl))-N-[3-(trifluoromethyl)phenyl]carboxamide

[0975] MS: (ES+) 408 (M+H); (ES−) 406. (M−H). Calc'd for C₂₀H₁₄F₅N₃O:407.34.

EXAMPLE 30

[0976]

(2-{[(2,3-Difluorophenyl)methyl]amino}(3-pyridyl))-N-[3-(trifluoromethyl)phenyl]carboxamide

[0977] MS: (ES+) 408 (M+H); (ES−) 406. (M−H). Calc'd for C₂₀H₁₄F₅N₃O:407.34.

EXAMPLE 31

[0978]

(2-{[(2-Fluorophenyl)methyl]amino}(3-pyridyl))-N-[3-(trifluoromethyl)phenyl]carboxamide

[0979] MS: (ES+) 390 (M+H); (ES−) 388. (M−H). Calc'd for C₂H₁₅F₄N3O:389.35.

EXAMPLE 32

[0980]

(2-{[(2,6-Difluorophenyl)methyl]amino}(3-pyridyl))-N-[3-(trifluoromethyl)phenyl]carboxamide

[0981] MS: (ES+) 408 (M+H); (ES−) 406. (M−H). Calc'd for C₂₀H₁₄F₅N₃O:407.34.

EXAMPLE 33

[0982]

(2-{[(3-Bromophenyl)methyl]amino}(3-pyridyl))-N-[3-(trifluoromethyl)phenyl]carboxamide

[0983] MS: (ES+) 451 (M+H); (ES−) 449. (M−H). Calc'd for C₂₀H₁₅BrF₃N₃O:450.26.

EXAMPLE 34

[0984]

(2-{[(4-Fluorophenyl)methyl]amino}(3-pyridyl))-N-[4-(trifluoromethyl)phenyl]carboxamide

[0985] MS: (ES+) 390 (M+H); (ES−) 388. (M−H). Calc'd for C₂₀H₁₅F₄N₃O:389.35.

EXAMPLE 35

[0986]

N-{3-[3-(Dimethylamino)propyl]-5-(trifluoromethyl)phenyl}(2-{[(4-fluorophenyl)methyl]amino}(3-pyridyl))carboxamide

[0987] Step A Preparation of{3-[3-amino-5-(trifluoromethyl)phenyl]propynyl}dimethylamine

[0988] A mixture of 3-bromo-5-trifluoromethylaniline (1.4 g, 5.9 mmol),1-dimethylamino-2-propyne (1.3 mL, 0.76 mmol), PdCl₂(PPh₃)₂ (0.26 g,0.29 mmol) and CuI (114 mg, 0.60 mmol) in 10 mL of TEA was heated at100° C. in a sealed tube for 3 h. The resulting mixture was filteredover Celite®. The filtrate was concentrated, and the residue waspurified by prep-HPLC (reverse phase) to give the aniline. MS (ES+): 243(M+H)⁺; (ES−): 241 (M−H)⁻. Calc'd C₁₂H₁₃F₃N₂-242.24.

[0989] Step B Preparation of{3-[3-amino-5-(trifluoromethyl)phenyl]propyl}dimethylamine

[0990] A mixture of the above aniline (7 g, 29 mmol) and Pd(OH)₂ (0.5 g)in 250 mL of MeOH was stirred under 50 psi H₂. After 2 h, the resultingmixture was filtered over Celite®. The filtrate was concentrated, andthe residue was diluted with aq. 1N HCl. The aq. layer was washed withEt₂O, made basic with aq. 5N NaOH, and extracted with CH₂Cl₂. Theorganic solution was dried over NaSO₄ and concentrated to give thetitled compound. MS (ES+): 386 (M+H)⁺; (ES−): 384 (M−H)⁻. Calc'dC₁₈H₁₉ClF₃N₃O-385.81.

[0991] Step C Preparation ofN-{3-[3-(dimethylamino)propyl]-5-(trifluoromethyl)phenyl}(2-{[(4-fluorophenyl)methyl]amino}(3-pyridyl))carboxamide

[0992] The title compound was analogously synthesized by the methoddescribed in Example 7. MS (ES+): 475(M+H)⁺; (ES−): 473(M−H)⁻. Calc'dC₂₅H₂₆F₄N₄O-474.50.

EXAMPLE 36

[0993]

{2-[({3-[3-(Dimethylamino)propyl]-4-fluorophenyl}methyl)amino](3-pyridyl)}-N-[4-(tert-butyl)phenyl]carboxamide

[0994] Step A Preparation of N-Boc-(3-bromo-4-fluoro-benzyl)amine

[0995] To a solution of 3-bromo-4-fluorobenzylamine hydrochloride (10 g,42 mmol) and TEA (10.5 g, 103 mmol) in 200 mL of CH₂Cl₂ was added BOC₂O(9.1 g, 42 mmol) at RT. The resulting solution was stirred for 16 h. Thesolution was diluted with aq. 1N NaOH and CH₂Cl₂. The organic layer waswashed with brine, dried over Na₂SO₄, and concentrated to giveN-Boc-(3-bromo-4-fluoro-benzyl)amine. MS (ES+): 305 (M+H)⁺; (ES−): 303(M−H). Calc'd C₁₂H₁₅BrFNO₂-304.16.

[0996] Step B Preparation of[3-(3-dimethylamino-propyl)-4-fluoro-benzyl]-Boc-axmine

[0997] [3-(3-Dimethylamino-propyl)-4-fluoro-benzyl]-Boc-amine wasprepared from N-Boc-(3-bromo-4-fluoro-benzyl)amine according to aprocedure similar to that described in Example 35, Step A.

[0998] Step C Preparation ofN-{3-[3-(dimethylamino)propyl]-4-fluorophenyl}methylamine

[0999] To [3-(3-Dimethylamino-propyl)-4-fluoro-benzyl]-Boc-amine (3.0 g,10 mmol) in 100 mL of CH₂Cl₂ was slowly added TFA (10 mL). The resultingsolution was stirred for 1 h, then concentrated. The residue was dilutedwith CH₂Cl₂ and aq. NaHCO₃ solution. The organic layer was dried overNa₂SO₄ and concentrated to give the title compound. MS (ES+): 211(M+H)⁺; (ES−): 209 (M−H). Calc'd C₁₂H₁₉FN₂-210.29.

[1000] Step D Preparation of{2-[({3-[3-(dimethylamino)propyl]-4-fluorophenyl}methyl)amino](3-pyridyl)}-N-[4-(tert-butyl)phenyl]carboxamide

[1001] The title compound was analogously synthesized by the methoddescribed in Example 7. MS (ES+): 463 (M+H)⁺; (ES−): 461 (M−H). Calc'dC₂₈H₃₅FN₄O-462.61.

[1002] The following compounds were analogously synthesized by themethod described in Example 36.

EXAMPLE 37

[1003]

{2-[({3-[3-(Dimethylamino)propyl]-4-fluorophenyl}methyl)amino](3-pyridyl)}-N-[4-(trifluoromethyl)phenyl]carboxamide

[1004] MS (ES+): 475 (M+H)⁺; (ES−): 473 (M−H). Calc'dC₂₅H₂₆F₄N₄O-474.50.

EXAMPLE 38

[1005]

{2-[({3-[3-(Dimethylamino)propyl]-4-fluorophenyl}methyl)amino](3-pyridyl)}-N-(4-bromo-2-fluorophenyl)carboxamide

[1006] MS (ES+): 504 (M+H)⁺; (ES−): 502 (M−H). Calc'dC₂₄H₂₅BrF₂N₄O-503.39.

EXAMPLE 39

[1007]

2-[(4-Fluorobenzyl)amino]-N-[4-tert-butyl-3-(1,2,3,6-tetrahydropyridin-4-yl)phenyl]nicotinamide

[1008] Step A Preparation of 2-bromo-1-tert-butyl-4-nitrobenzene

[1009] NBS (125.0 g, 697.5 mmol, 1.5 eq) was slowly added to a solutionof TFA:H₂SO₄ (5:1, 750 mL) and tert-butyl-4-nitrobenzene (100.0 g, 558.0mmol) at RT. The solution was stirred for 24 h then poured over 5 kg ofice. The resulting suspension was filtered, washed with a 1:1 MeOH:H₂Osolution (200 mL) and dried in a vacuum oven. MS (ES+): 258.1, 260.1(M+H)⁺

[1010] Step B Preparation of 4-(2-tert-butyl-5-nitrophenyl)pyridine

[1011] To a solution of 2-bromo-1-tert-butyl-4-nitrobenzene (8.6 g, 33.3mmol) (Step A) and toluene (70 mL) in a 150 mL round bottom flask,4-pyridylboronic acid (4.5 g, 36.6 mmol, 1.1 eq), Pd(PPh₃)₄ (3.8 g, 3.3mmol, 0.1 eq) and K₂CO₃ (13.8 g, 99.9 mmol, 3 eq) were added. Thesolution was stirred for 24 h at 80° C. The solution was filteredthrough a pad of Celite® and purified by silica flash chromatography(30% Hex/Hex) to afford the desired compound as a yellow solid. MS(ES+): 257.2 (M+H)⁺; (ES−): 255.2 (M−H)⁻.

[1012] Step C Preparation of4-(2-tert-butyl-5-nitrophenyl)-1-methylpyridinium

[1013] 4-(2-tert-Butyl-5-nitrophenyl)pyridine (2.0 g, 7.8 mmol) (Step B)was added to a round-bottom flask and dissolved in EtOH (10 mL). CH₃I(30mL) was added to the flask and heated to reflux. After 6 h, the solutionwas cooled to RT and concentrated in vacuo resulting in the desiredcompound as a light brown solid. MS (ES+): 271.2 (M+H)⁺; (ES−): 269.2(M−H)⁻. Calc'd for C₁₆H₁₉N₂O₂: 271.14.

[1014] Step D: Preparation of4-tert-butyl-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)aniline

[1015] 4-(2-tert-Butyl-5-nitrophenyl)-1-methylpyridinium (2.1 g, 7.8mmol) (Step C) was added to a 100 mL round-bottom flask and dissolved ina 10% H₂O/EtOH mixture. Iron dust (1.31 g, 23.4 mmol, 3 eq) and NH₄Cl(460 mg, 8.6 mmol, 1.1 eq) were added. The flask was heated to reflux.After 2 h, the solution was cooled to RT and filtered through a pad ofCelite®. The resulting solution was stripped down to a yellow solid andredissolved in MeOH (20 mL, anhydrous). The solution was cooled to 0° C.and slowly adding NaBH₄ (450 mg, 11.7 mmol, 1.5 eq). The solution wascooled to RT and stirred for 30 min. The solvent was stripped-off undervacuum and the solid was redissolved in CH₂Cl₂ and filtered. Thesolution was concentrated in vacuo to afford an amorphous clear yellowsolid. MS (ES+): 245.2 (M+H)⁺

[1016] Step E: Preparation of2-[(4-fluorobenzyl)amino]-N-[4-tert-butyl-3-(1,2,3,6-tetrahydropyridin-4-yl)phenyl]nicotinamide

[1017] The title compound was analogously synthesized by the methoddescribed in Example 7. MS: (ES+) 473.2 (M+H); (ES−) 471.4 (M−H). Calc'dfor C₂₉H₃₃FN₄O: 472.60.

EXAMPLE 40

[1018]

[2-({[4-Fluoro-3-(3-morpholin-4-ylprop-1-ynyl)phenyl]methyl}amino)(3-pyridyl)]-N-[3-(trifluoromethyl)phenyl]carboxamide

[1019] Step A: Preparation of(tert-butoxy)-N-[(3-bromo-4-fluorophenyl)methyl]carboxamide

[1020] To a solution of 3-bromo-4-fluorobenzylamine (10 g, 41 mmol) andTEA (14 mL, 104 mmol) in CH₂Cl₂ was added BOC₂O (9.1 g, 41 mmol). Theresulting solution was stirred for 16 h at RT, then diluted with aq. 1NNaOH and CH₂Cl₂. The organic layer was separated, washed with brine,dried over Na₂SO₄, and concentrated to give(tert-butoxy)-N-[(3-bromo-4-fluorophenyl)methyl]carboxamide.

[1021] Step B: Preparation of(tert-Butoxy)-N-{[4-fluoro-3-(3-hydroxyprop-1-ynyl)phenyl]methyl}carboxamide

[1022] A mixture oftert-butoxy-N-[(3-bromo-4-fluorophenyl)methyl]carboxamide (0.6 g, 2.0mmol, Step A), CuI (38 mg, 0.2 mmol), PdCl₂(PPh₃)₂ (72 mg, 0.1 mmol),propargyl alcohol (0.35 mL, 6.0 mmol) and TEA (12 mL) was heated at 100°C. for 5 h. The resulting mixture was filtered, and the filtrate wasconcentrated. The residue was purified by SiO₂ chromatography to givethe title compound. MS (ES+): 297 (M+NH4)⁺. Calc'd C₁₅H₂₂FN₂O₃-297.34.

[1023] Step C: Preparation of[4-Fluoro-3-(3-morpholin-4-ylprop-1-ynyl)phenyl]-methylamine

[1024] To a mixture of(tert-butoxy)-N-{[4-fluoro-3-(3-hydroxyprop-1-ynyl)phenyl]methyl]carboxamide(0.23 g, 0.82 mmol) (Step B) and NMO (0.14 g, 1.3 mmol) was addedcatalytic amount of TPAP. The resulting mixture was stirred for 1 h atRT, then filtered over a short pad of SiO₂ and concentrated. To asolution of the residue and morpholine (0.1 mL, 1.2 mmol) in CH₂Cl₂ wasadded excess NaBH(OAc)₃. The resulting solution was stirred for 16 h,diluted with CH₂Cl₂ and saturated aq. NaHCO₃ solution. The organic layerwas separated, dried over Na₂SO₄, and concentrated. The residue waspurified by SiO₂ chromatography to give a colorless oil, which wasdissolved in 5 mL of CH₂Cl₂. To the organic solution was added TFA (2mL). The resulting solution was stirred for 1 h at RT, thenconcentrated. The residue was diluted with CH₂Cl₂ and saturated aq.NaHCO₃ solution. The organic layer was separated, dried over Na₂SO₄, andconcentrated to give the title compound. MS (ES+): 249 (M+H)⁺; (ES−):247. Calc'd C₁₄H₁₇FN₂O-248.30.

[1025] Step D: Preparation of[2-({[4-fluoro-3-(3-morpholin-4-ylprop-1-ynyl)phenyl]methyl}amino)(3-pyridyl)]-N-[3-(trifluoromethyl)phenyl]carboxamide

[1026] The title compound was analogously synthesized by the methoddescribed in Example 7. MS (ES+): 513 (M+H)⁺; (ES−): 511. Calc'dC₂₇H₂₄F₄N₄O₂-512.51.

EXAMPLE 41

[1027]

(2-[(2H-Benzo[d]1,3-dioxol-5-ylmethyl)amino](3-pyridyl)}-N-(4-phenoxyphenyl)carboxamide

[1028] 2-Chloro-(3-pyridyl)-N-(4-phenoxyphenyl)-carboxamide (0.500 g,1.5 mmol) and 2H-benzo[d]1,3-dioxolan-5-ylmethylamine (0.680 g, 4.5mmol) were combined and heated neat at 110° C. for 18 h. After coolingto RT, the resulting residue was dissolved in EtOAc and washed withsaturated NaACO₃ solution and brine, respectively. The organics weredried over Na₂SO₄ and evaporated. The crude material was purified bycolumn chromatography with EtOAc/hexanes (1:2) as eluant to leave thedesired compound as an off-white solid. MS: (ES+) 440 (M+1)⁺; (ES−): 438(M−1)⁻. Calc'd. for C₂₆H₂₁N₃O₄-439.15.

EXAMPLE 42

[1029]

2-(4-Fluoro-benzylamino)-N-[3-(2-pyrrolidin-1-yl-ethoxy)-4-trifluoromethyl-phenyl]-nicotinamide

[1030]2-Chloro-N-[3-(2-pyrrolidin-1-yl-ethoxy)-4-trifluoromethyl-phenyl]-nicotinamide(199.1 mg), DIEA (252 uL) and 4-fluorobenzylamine (193 μL) were combinedin a sealed tube and heated to 130° C. for 2 h. The mixture was purifiedon silica gel chromatography (2-3.5% MeOH/CH₂Cl₂). The desired fractionswere concentrated in vacuo, and the residue was dissolved in Et₂O andhexanes were added until the solution became cloudy. The solids werefiltered, and dried. Additional material was obtained from the filtrateupon additional rounds of concentration, dissolving in Et₂O andtreatment with hexanes. M+H 503.4, Calc'd for C₂₆H₂₆N₄O₂F₄-502.2.

EXAMPLE 43

[1031]

(R)2-(4-Fluoro-benzylamino)-N-[3-(1-Boc-pyrrolidin-2-ylmethoxy)-4-pentafluoroethyl-phenyl]-nicotinamide

[1032]2-Chloro-N-[3-(1-Boc-pyrrolidin-2-ylmethoxy)-4-pentafluoroethyl-phenyl]-nicotinamide(442.8 mg) DIEA (351 μL) and 4-fluorobenzylamine (322 μL) were combinedin a sealed tube and heated to 130° C. for 3 h. The mixture was dilutedwith EtOAc and H₂O, the layers were separated and the organic layer waswashed with brine, dried over Na₂SO₄, filtered and concentrated invacuo. The residue was purified with silica gel chromatography (1%MeOH/CH₂Cl₂) to obtain an off-white solid.

EXAMPLE 44

[1033]

N-[4-tert-Butyl-3-(1-Boc-piperidin-4-ylmethoxy)-phenyl]-2-(4-fluoro-benzylamino)-nicotinamide

[1034]N-[4-tert-Butyl-3-(1-Boc-piperidin-4-ylmethoxy)-phenyl]-2-chloro-nicotinamide(200 mg), DIEA (145 μL), IpOH (3 ml) and 4-fluorobenzylamine (184 μL)were combined in a sealed tube and heated to 125° C. for 2 days. Themixture was purified by flash chromatography (EtOAc) to provide theproduct. M+Na 619; Calc'd for C₃₄H₄₃FN₄O₄: 590.33.

EXAMPLE 45

[1035]

N-[3,3-Dimethyl-1-(1-methyl-piperidin-4-yl)-2,3-dihydro-1H-indol-6-yl]-2-(4-fluoro-benzylamino)-nicotinamide

[1036] A solution ofN-[3,3-dimethyl-1-(1-methyl-piperidin-4-yl)-2,3-dihydro-1H-indol-6-yl]-2-fluoro-nicotinamide(500 mg), 4-fluorobenzylamine (240 μL) and NaHCO₃ (359 mg) was dissolvedin IpOH (5 ml) and heated to 85 ° C. overnight. After cooling to RT, themixture was dried under N₂. The residue was partitioned between EtOAcand H₂O, the organic layer was separated, washed with brine, dried overNa₂SO₄ and filtered. Silica was added to the filtrate and concentratedto a residue. It was purified by flash chromatography (10% MeOH/EtOAc)to yield a fluffy yellow solid. M+H 488.4. Calc'd for C₂₉H₃₄FN₅O: 487.3.

[1037] The following compounds (Examples 46-53) were analogously formedfrom the corresponding fluoro compounds by the method described inExample 45.

[1038] 46)N-[1-(2-Dimethylamino-acetyl)-3,3-dimethyl-2,3-dihydro-1H-indol-6-yl]-2-(4-fluoro-benzylamino)-nicotinamide.M+H 476.3; Calc'd 475.24.

[1039] 47)N-[1-(1-Boc-piperidin-4-yl)-3,3-dimethyl-2,3-dihydro-1H-indol-6-yl]-2-(4-fluoro-benzylamino)-nicotinamide.M+H 574.5; Calc'd 573.31.

[1040] 48)N-[3,3-Dimethyl-1-(2-Boc-amino-acetyl)-2,3-dihydro-1H-indol-6-yl]-2-(4-fluoro-benzylamino)-nicotinamide.M+H 548.4.

[1041] 49)2-(4-Fluoro-benzylamino)-N-(2-Boc-4,4-dimethyl-1,2,3,4-tetrahydro-isoquinolin-7-yl)-nicotinamide.M+H 505.4.

[1042] 50)N-[3-(1-Boc-pyrrolidin-2-ylmethoxy)-5-trifluoromethyl-phenyl]-2-(4-fluoro-benzylamino)-nicotinamidewas prepared as above but at 90C. overnight and with a second additionof amine prior to heating for another 24 h. M+Na 611. Calc'd 588.2.

[1043] 51)N-[4-tert-Butyl-3-(1-Boc-pyrrolidin-2-ylmethoxy)-phenyl]-2-(4-fluoro-benzylamino)-nicotinamide.M+Na 599. Calc'd 576.31.

[1044] 52)N-(4-Acetyl-2,2-dimethyl-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl)-2-(4-fluoro-benzylamino)-nicotinamidewas prepared as described above but substituting t-BuOH for IpOH andheating overnight at 80C. M+H 449.1; Calc'd 448.19.

[1045] 53)2-(4-Fluoro-benzylamino)-N-[3-(1-Boc-piperidin-4-ylmethoxy)-5-trifluoromethyl-phenyl]-nicotinamide.M+H 603.4.

EXAMPLE 54

[1046]

(R)2-(4-Fluoro-benzylamino)-N-[3-(pyrrolidin-2-ylmethoxy)-4-pentafluoroethyl-phenyl]-nicotinamide

[1047]2-(4-Fluoro-benzylamino)-N-[3-(1-Boc-pyrrolidin-2-ylmethoxy)-4-pentafluoroethyl-phenyl]-nicotinamide(Example 43) was dissolved in CH₂Cl₂ (8 ml) and TFA (8 ml) was added.After stirring at RT for 70 min, the mixture was concentrated in vacuo,diluted with 2N NaOH and CH₂Cl₂. The layers were separated and theaqueous layer was back extracted with CH₂Cl₂. The organic layer waswashed with brine, dried over Na₂SO₄, filtered and concentrated in vacuoto provide an light pink-orange solid. M+H 539.5. Calc'd forC₂₆H₂₄F₆N₄O₂: 538.2.

[1048] The following compounds (Examples 55-59) were analogously formedfrom the corresponding Boc-protected compounds by the method describedin Example 54.

[1049] 55) (R)2-(4-Fluoro-benzylamino)-N-[3-(pyrrolidin-2-ylmethoxy)-5-trifluoromethyl-phenyl]-nicotinamide.M+H 489; Calc'd 488.2.

[1050] 56)N-[4-tert-Butyl-3-(piperidin-4-ylmethoxy)-phenyl]-2-(4-fluoro-benzylamino)-nicotinamide.M+H 491; Calc'd 490.3.

[1051] 57) (R)N-[4-tert-Butyl-3-(pyrrolidin-2-ylmethoxy)-phenyl]-2-(4-fluoro-benzylamino)-nicotinamide.M+H 477; Calc'd 476.3.

[1052] 58)N-(4,4-Dimethyl-1,2,3,4-tetrahydro-isoquinolin-7-yl)-2-(4-fluoro-benzylamino)-nicotinamide.M+H 405.1; Calc'd 404.2.

[1053] 59)N-[1-(2-Amino-acetyl)-3,3-dimethyl-2,3-dihydro-1H-indol-6-yl]-2-(4-fluoro-benzylamino)-nicotinamide.

EXAMPLE 60

[1054]

N-(3,3-Dimethyl-1-piperidin-4-yl-2,3-dihydro-1H-indol-6-yl)-2-(4-fluoro-benzylamino)-nicotinamide

[1055]N-[1-(1-Boc-piperidin-4-yl)-3,3-dimethyl-2,3-dihydro-1H-indol-6-yl]-2-(4-fluoro-benzylamino)-nicotinamide(Example 47) was dissolved in a mixture of conc. HCl and EtOAc andstirred at RT for 1.5 h. The mixture was concentrated in vacuo and theresidue was partitioned between EtOAc and 1N NaOH. The organic layer wasremoved, washed with brine, dried over Na₂SO₄, filtered and concentratedin vacuo to provide a yellow solid. M+H 474.3. Calc'd for C₂₈H₃₂FN₅O:473.3.

EXAMPLE 61

[1056]

2-(4-Fluoro-benzylamino)-N-[3-(piperidin-4-ylmethoxy)-5-trifluoromethyl-phenyl]-nicotinamide

[1057]2-(4-Fluoro-benzylamino)-N-[3-(piperidin-4-ylmethoxy)-5-trifluoromethyl-phenyl]-nicotinamidewas prepared by a method similar to that described for Example 60. M+H503.3. Calc'd for C₂₆H₂₆F₄N₄O₂: 502.2.

EXAMPLE 62

[1058]

N-(2,2-Dimethyl-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl)-2-(4-fluoro-benzylamino)-nicotinamide

[1059]N-(4-Acetyl-2,2-dimethyl-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl)-2-(4-fluoro-benzylamino)-nicotinamide(250 mg, Example 52) was dissolved in EtOH (10 ml) and treated withconc. HCL (0.5 ml) at 60° C. for 16 h. The mixture was cooled to 0° C.and sat. NaHCO₃ (aq) was added. The mixture was extracted with EtOAc(3×50 ml) and the combined organic fractions were washed with brine,dried over Na₂SO₄, filtered and concentrated in vacuo. The residue waspurified by silica gel chromatography (50% EtOAc/hexanes). M+H 407.3;Calc'd for C₂₃H₂₃FN₄O₂: 406.18.

EXAMPLE 63

[1060]

(S)-2-(4-Fluoro-benzylamino)-N-[3-(1-methyl-pyrrolidin-2-ylmethoxy)-5-trifluoromethyl-phenyl]-nicotinamide

[1061]2-Fluoro-N-[3-(1-methyl-pyrrolidin-2-ylmethoxy)-5-trifluoromethyl-phenyl]-nicotinamide(300 mg), TEA (314 uL) and 4-fluorobenzylamine (170 μL) were combined ina sealed tube and heated to 90° C. for 3 h. Cooled to RT and the mixturewas diluted with EtOAc, washed with sat. NH₄Cl (2×), brine, dried overNa₂SO₄, filtered and concentrated in vacuo. The residue was purified bysilica gel chromatography (CH₂Cl₂/MeOH/NH₄OH 95/5/0.5) to provide anoff-white foam upon drying. M+H 503. Calc'd for C₂₆H₂₆F₄N₄O₂: 502.20.

EXAMPLE 64

[1062]

N-[3,3-Dimethyl-1-(1-methyl-piperidin-4-ylmethyl)-2,3-dihydro-1H-indol-6-yl]-2-(4-fluoro-benzylamino)-nicotinamide

[1063] ToN-(3,3-dimethyl-1-piperidin-4-ylmethyl-2,3-dihydro-1H-indol-6-yl)-2-(4-fluoro-benzylamino)-nicotinamide(0.92 g) dissolved in DCE (20 ml) at RT was added formaldehyde (37%aqueous, 0.42 mL) followed by NaBH(OAc)₃ (1.59 g). After 4 h, themixture was quenched with 1N HCl. (20 mL) and H₂O (20 mL). It wasbasified with sat NaHCO₃, extracted with CH₂Cl₂ (3×50 mL) and thecombined extracts were washed with brine, dried (K₂CO₃) and concentratedonto SiO₂ (previously treated with 10% MeOH (2M NH₃ in MeOH/CH₂Cl₂ andthen concentrated in vacuo). The residue was purified by flashchromatography (Isco, 35 g column, 1-7% MeOH (2M NH₃ in MeOH/CH₂Cl₂).The bulk of the crude yellow material was further purified by reversephase Prep HPLC. The isolated fractions were partially concentrated andbasified with 1N NaOH and dried under vacuum to afford a slightly yellowpowder. M+H=502.3. Calc'd for C₃₀H₃₆FN₅O: 501.29.

EXAMPLE 65

[1064]

2-(4-Fluoro-benzylamino)-N-{4-[1-methyl-1-(1-methyl-piperidin-4-yl)-ethyl]-phenyl}-nicotinamide

[1065] A solution of2-fluoro-N-{4-[1-methyl-1-(1-methyl-piperidin-4-yl)-ethyl]-phenyl}-nicotinamide(355 mg) and 4-fluorobenzylamine (250 mg) in pyridine (10 mL) wassuspended with NaHCO₃ (1 g). The mixture was heated to 105° C.overnight. Solids were removed by filtration and the filtrate wasconcentrated in vacuo. The residue was purified on prep. TLC. plates(silica, EtOAc:TEA=10:1) to provide the desired product. MS (ES+): 461(M+1)⁺, Calc'd for C₂₈H₃₃FN₄O-460.59.

EXAMPLE 66

[1066]

N-(4,4-Dimethyl-2-oxo-1,2,3,4-tetrahydro-quinolin-7-yl)-2-(4-fluoro-benzylamino)-nicotinamide

[1067] M+H 419.1. Calc'd for C₂₄H₂₃FN₄O₂: 418.2.8

EXAMPLE 67

[1068]

3-Benzo[1,3]dioxol-5-yl-3-[3-(4-pentafluoroethyl-phenylcarbamoyl)-pyridin-2-ylamino]-propionicacid

[1069] The Compound was synthesized by a procedure similar to the methoddescribed in Example 45. M+H 524.1. Calc'd for C₂₅H₂₀F₅N₃O₅: 537.13.

EXAMPLE 68

[1070]

N-(3,3-Dimethyl-1-(methylsulfonyl)-2,3-dihydro-1H-indol-6-yl)-2-(((4-fluorophenyl)methyl)amino)-3-pyridinecarboxamide

[1071] Calc'd for C₂₄H₂₅FN₄O₃S-468.55; M+H−469.1.

EXAMPLE 69

[1072]

N-(4-(1,1-Dimethylethyl)-3-((N,N-dimethylglycyl)amino)phenyl)-2-(((4-fluorophenyl)methyl)amino)-3-pyridinecarboxamide

[1073] Calc'd for C₂₇H₃₂FN₅O₂-477.581; M+H 478.

EXAMPLE 70

[1074]

2-(((4-Fluorophenyl)methyl)amino)-N-(3-((((2R)-1-methyl-2-pyrrolidinyl)methyl)oxy)-5-(trifluoromethyl)phenyl)-3-pyridinecarboxamide

[1075] C₂₆H₂₆F₄N₄O₂-502.509; M+H 503.

EXAMPLE 71

[1076]

2-(((4-Fluorophenyl)methyl)amino)-N-(3-((methylsulfonyl)amino)-5-(trifluoromethyl)phenyl)-3-pyridinecarboxamide

[1077] C₂₁H₁₈F₄N₄O₃S-482.456; M+H 483, M+Na 505.

EXAMPLE 72

[1078]

2-(((4-Fluorophenyl)methyl)amino)-N-(4-(1-methyl-1-(5-methyl-1,3,4-oxadiazol-2-yl)ethyl)phenyl)-3-pyridinecarboxamide

[1079] MS: 446 (M+1); Calc'd for C₂₅H₂₅FN₅O₂-445.19.

EXAMPLE 73

[1080]

3-(2-Chloro-5-{[2-(4-fluoro-benzylamino)-pyridine-3-carbonyl]-amino}-phenoxymethyl)-azetidine-1-carboxylicacid tert-butyl ester

[1081] MS (ES⁺): 542 (M+H)⁺. Calc'd for C₂₈H₃₀ClFN₄O₄-541.02

EXAMPLE 74

[1082]

N-[3-(Azetidin-3-ylmethoxy)-4-chloro-phenyl]-2-(4-fluoro-benzylamino)-nicotinamide

[1083] To a solution of 10 mL of TFA/CH₂Cl₂ (1:1) was added3-(2-chloro-5-{[2-(4-fluoro-benzylamino)-pyridine-3-carbonyl]-amino}-phenoxymethyl)-azetidine-1-carboxylicacid tert-butyl ester (270 mg, 0.5 mmol) at 0° C. The solution wasstirred for 2 h at RT. The solvents were removed in vacuo. The residuewas diluted in 30 mL of EtOAc and washed with 30 mL of saturated aqueousNaHCO₃, then brine. The resulting organic phase was dried over MgSO₄ andconcentrated in vacuo. The title compound was purified by columnchromatography (silica gel, 5% 2N NH₃ in MeOH/EtOAc) and isolated as awhite solid. MS (ES⁺): 442 (M+H)⁺. Calc'd for C₂₃H₂₂ClFN₄O₂-440.90.

EXAMPLE 75

[1084]

6-Chloro-3-(4-fluoro-benzylamino)-pyridazine-4-carboxylic acid(4-tert-butyl-phenyl)-amide

[1085] A mixture of3-(benzotriazol-1-yloxy)-6-chloro-pyridazine-4-carboxylic acid(4-tert-butyl-phenyl)-amide (0.348 g, 0.82 mmol) and 4-fluorobenzylamine(1.0 ml, 8.75 mmol) was stirred at 60° C. under N₂ for 30 min, cooled toRT, and purified by flash column chromatography. The desired compoundwas obtained as a solid. MS (ES⁺): 413.0 (M+H)⁺. Calc'd forC₂₂H₂₂ClFN₄O-412.89.

EXAMPLE 76

[1086]

3-(4-Fluoro-benzylamino)-pyridazine-4-carboxylic acid(4-tert-butyl-phenyl)-amide

[1087] A mixture of6-chloro-3-(4-fluoro-benzylamino)-pyridazine-4-carboxylic acid(4-tert-butyl-phenyl)-amide (0.210 g, 0.51 mmol) and Pd/C. (50 mg, 10%weight) in 10 ml of MeOH was placed under H₂ from a balloon and stirredat RT for 26 h, filtered through Celite®, condensed, and purified byflash column chromatography (0.5% to 2% of MeOH in CH₂Cl₂, then 1% ofMeOH and 1% of NH₄OH in CH₂Cl₂). The titled product was obtained as alight yellowish solid. MS (ES⁺): 379.0(M+H)⁺. Calc'd forC₂₂H₂₃FN₄O-378.44.

EXAMPLE 77

[1088]

3-(4-Fluoro-benzylamino)-1,2,5,6-tetrahydro-pyridazine-4-carboxylic acid(4-tert-butyl-phenyl)-amide

[1089] The titled compound was prepared in the same method as that ofExample 76, and isolated as a light yellowish solid. MS (ES⁺): 383.0(M+H)⁺. Calc'd for C₂₁H₂₃N₅O-382.47.

EXAMPLE 78

[1090]

N-[3-(Azetidin-3-ylmethoxy)-5-trifluoromethyl-phenyl]-2-(4-fluoro-benzylamino)-nicotinamide

[1091] The title compound was synthesized from3-(3-amino-5-trifluoromethyl-phenoxymethyl)-azetidine-1-carboxylic acidbenzyl ester analogous to that described for Example 74. MS (ES+): 475.1(M+H)⁺. Calc'd. for C₂₈H₃₄N₄O-474 5.

EXAMPLE 79

[1092]

2-(4-Hydroxy-3-nitro-benzylamino)-N-(4-isopropyl-phenyl)-nicotinamide

[1093] MS: (ES+) 407 (M+H). Calc'd for C₂₂H₂₂N₄O₄-406.45.

EXAMPLE 80

[1094]

2-(4-Hydroxy-3-amino-benzylamino)-N-(4-isopropyl-phenyl)-nicotinamide

[1095] MS: (ES+) 377 (M+H). Calc'd for C₂₂H₂₄N₄O₂-376.45.

[1096] Other compounds included in this invention are set forth inTables 1-3 below. TABLE 1

# R¹ R² R⁸ 81. 4-chlorophenyl H 4-amino- 82. 3-isoquinolinyl H 83.2-quinolinyl H 84. 2-benzthiazolyl H 85. 2-benzimidazolyl H 4-amino- 86.4-benzimidazolyl H 87. 5-benzimidazolyl H 88. 6-benzimidazolyl H 89.7-benzimidazolyl H 90. 2-chlorophenyl 5-Br 91. 3-isoquinolinyl 5-Br 92.2-quinolinyl 5-Br 93. 2-benzthiazoyl 5-Br 94. 2-benzimidazolyl 5-Br 95.4-benzimidazolyl 5-Br 96. 5-benzimidazolyl 5-Br 97. 6-benzimidazolyl5-Br 4-amino- 98. 7-benzimidazolyl 5-Br 4-amino- 99. 4-chlorophenyl 5-Br3-amino 100. 4-chlorophenyl 5-Br 4-hydroxy 101. 4-chlorophenyl 6-CH₃4-amino- # R² R¹ R⁸ 102. 4-phenoxyphenyl H 4-amino 103. 3-phenoxyphenylH 4-methoxy 104. 4-biphenyl H 4-methoxy 105. 4-cyclohexylphenyl H4-methoxy 106. 2-quinolyl H 4-methoxy 107. 3-isoquinolyl H 4-methoxy108. 3-quinolyl H 4-methoxy 109. 1-isoquinolyl H 4-methoxy 110.5-quinolyl H 4-methoxy 111. 5-isoquinolyl H 4-methoxy 112. 6-quinolyl H4-methoxy 113. 6-isoquinolyl H 4-methoxy 114. 7-quinolyl H 4-methoxy115. 7-isoquinolyl H 4-hydroxy 116. 4-quinolyl H 4-hydroxy 117.4-isoquinolyl H 4-hydroxy 118. 4-pyridyl H 4-hydroxy 119. 4-pyrimidinylH 4-hydroxy 120. 2-pyrimidinyl H 4-hydroxy 121. 6-pyrimidinyl H4-hydroxy 122. 4-pyridazinyl H 4-hydroxy 123. 5-pyridazinyl H 4-hydroxy124. 4-indolyl H 4-hydroxy 125. 5-isoindolyl H 3-amino 126.5-naphthyridinyl H 3-amino 127. 6-quinozalinyl H 3-amino 128.6-isoquinolyl H 3-amino 129. 4-naphthyridinyl H 3-amino 130.5-quinozalinyl H 3-amino 131. 4-naphthyridinyl H 3-amino 132.3,4-dichlorophenyl H 2-cyano 133. 6-isoquinolyl H 2-cyano 134.4-chlorophenyl H 3-cyano 135. 4-chlorophenyl H 4-cyano 136. 6-indazolylH 3-hydroxymethyl 137. 6-isoindolyl H 3-hydroxymethyl 138. 5-indazolyl H3-hydroxymethyl 139. 5-isoindolyl H 3-hydroxymethyl 140. 6-benzothienylH 3-hydroxymethyl 141. 6-benzofuryl H 3-hydroxymethyl 142.5-benzothienyl H 3-hydroxymethyl 143. 5-benzofuryl H 3-hydroxymethyl144. 2-benzimidazolyl H 3-hydroxymethyl 145. 2-benzoxazolyl H3-hydroxymethyl 146. 6-benzimidazolyl H 3-hydroxymethyl 147.6-benzoxazolyl H 3-hydroxymethyl 148. 6-benzthiazolyl H 4-amino 149.2-quinazolinyl H 4-hydroxymethyl 150. 3-(phenoxy)-6-pyridyl H3-aminocarbonyl 151. 4-(phenylcarbonyl)phenyl H 3-aminocarbonyl 152.4-(phenylamino)phenyl H 3-aminocarbonyl 153. 4-cyclohexyloxyphenyl H3-aminocarbonyl 154. 4-(3-thienyl)phenyl H 4-amino 155.4-(pyrazol-3-yl)phenyl H 4-amino 156. 4-pyridyl 6-Cl 4-amino, 3-F 157.3-methoxyphenyl 6-Cl 4-amino, 3-F 158. 4-hydroxyphenyl 6-Cl 4-amino, 3-F159. 3-hydroxyphenyl H 4-methoxy, 3-F 160. 2-hydroxyphenyl H 3-methoxy,3-F 161. 4-chlorophenyl 6-phenyl 4-amino 162. 4-phenoxyphenyl 6-phenyl4-amino 163. 4-biphenyl 6-phenyl 4-amino 164. 4-hydroxyphenyl 6-phenyl4-amino 165. 4-cyclohexylphenyl 6-phenyl 4-amino 166. 3-isoquinolyl6-phenyl 4-amino

[1097] TABLE 2

# R⁸ R² R¹ 154. 4-amino- 4-chlorophenyl H 155. 4-amino- 3-isoquinolinylH 156. 4-amino- 2-quinolinyl H 157. 4-amino- 2-benzthiazolyl H 158.4-amino- 2-benzimidazolyl H 159. 4-amino- 4-benzimidazolyl H 160.4-amino- 5-benzimidazolyl H 161. 4-amino- 6-benzimidazolyl H 162.4-amino- 7-benzimidazolyl H 163. 4-amino- 2-chlorophenyl 5-Br 164.4-amino- 3-isoquinolinyl 5-Br 165. 4-amino- 2-quinolinyl 5-Br 166.4-amino- 2-benzthiazolyl 5-Br 167. 4-amino- 2-benzimidazolyl 5-Br 168.4-amino- 4-benzimidazolyl 5-Br 169. 4-amino- 5-benzimidazolyl 5-Br 170.4-amino- 6-benzimidazolyl 5-Br 171. 4-amino- 7-benzimidazolyl 5-Br 172.3-amino- 4-chlorophenyl 5-Br 173. 4-hydroxy- 4-chlorophenyl 5-Br 174.4-amino- 4-chlorophenyl 6-CH₃ # R² R¹ R⁸ 175. 4-phenoxyphenyl H 4-amino176. 3-phenoxylphenyl H 4-methoxy 177. biphenyl H 4-methoxy 178.4-cyclohexylphenyl H 4-methoxy 179. 2-quinolyl H 4-methoxy 180.3-isoquinolyl H 4-methoxy 181. 3-quinolyl H 4-methoxy 182. 1-isoquinolylH 4-methoxy 183. 5-quinolyl H 4-methoxy 184. 5-isoquinolyl H 4-methoxy185. 6-quinolyl H 4-methoxy 186. 6-isoquinolyl H 4-methoxy 187.7-quinolyl H 4-methoxy 188. 7-isoquinolyl H 4-hydroxy 189. 4-quinolyl H4-hydroxy 190. 4-isoquinolyl H 4-hydroxy 191. 4-pyridyl H 4-hydroxy 192.4-pyrimidinyl H 4-hydroxy 193. 2-pyrimidinyl H 4-hydroxy 194.6-pyrimidinyl H 4-hydroxy 195. 4-pyridazinyl H 4-hydroxy 196.5-pyridazinyl H 4-hydroxy 197. 4-indolyl H 4-hydroxy 198. 5-isoindolyl H3-amino 199. 5-naphthyridinyl H 3-amino 200. 6-quinozalinyl H 3-amino201. 6-isoquinolyl H 3-amino 202. 4-naphthyridinyl H 3-amino 203.5-quinozalinyl H 3-amino 204. 4-naphthyridinyl H 3-amino 205.6-indazolyl H 3-hydroxymethyl 206. 6-isoindolyl H 3-hydroxymethyl 207.5-indazolyl H 3-hydroxymethyl 208. 5-isoindolyl H 3-hydroxymethyl 209.6-benzothienyl H 3-hydroxymethyl 210. 6-benzofuryl H 3-hydroxymethyl211. 5-benzothienyl H 3-hydroxymethyl 212. 5-benzofuryl H3-hydroxymethyl 213. 2-benzimidazolyl H 3-hydroxymethyl 214.2-benzoxazolyl H 3-hydroxymethyl 215. 2-benzthiazolyl H 3-hydroxymethyl216. 6-benzimidazolyl H 3-hydroxymethyl 217. 6-benzoxazolyl H3-hydroxymethyl 218. 6-benzthiazolyl H 4-amino 219. 2-quinazolinyl H4-hydroxymethyl

[1098] TABLE 3

# R⁸ Y R² R¹ 220. 4-F —NHSO₂— 4-chlorophenyl H 221. 4-F —NHSO₂—4-chlorophenyl 5-Br 222. 3,4- —NHSO₂— 3-chlorophenyl H diF 223. 4-Cl—NHSO₂— 3-chlorophenyl 5-Br 224. H —NHSO₂— 4-phenoxyphenyl H 225. 4-F—NHSO₂— 4-biphenyl H 226. 4-F —NHSO₂— 3-isoquinolyl H 227. 3,4- —NHSO₂—3-isoquinolyl 5-Br diF 228. H —NHSO₂— 4-chlorophenyl H 229. 4-F —NHSO₂—4-chlorophenyl 5-Br 230. 4-F —NHSO₂— 3-chlorophenyl H 231. 3,4- —NHSO₂—3-chlorophenyl 5-Br diF 232. H —NHSO₂— 4-phenoxyphenyl H 233. 4-F—NHSO₂— 4-biphenyl H 234. 4-F —NHSO₂— 3-isoquinolyl H 235. 3,4- diF—NHSO₂— 3-isoquinolyl 5-Br 236. H —NHCH₂—

H 237. 4-F —NHCH₂—

H 238. 4-F —NHCH₂—

H 239. 4-F —NHCH₂—

H 240. 4-F —NHCH₂— 3-CF₃-phenyl F 241. 4-F —NHCH₂—

H 242. 4-F —NHCH₂—

H 243. 3,4- diF —NHCH₂—

H 244. H —NHCH₂—

H 245. 4-F —NHCH₂—

H 246. 4-F —NHCH₂—

H 247. 4-F —NHCH₂—

H 248. 3,4- diF —NHCH₂—

H 249. H —NHCH₂—

H 250. 4-F —NHCH₂—

H 251. 4-F —NHCH₂—

H 252. 3,4- diF —NHCH₂—

H 253. H —NHCH₂—

H 254. 4-F —NHCH₂—

H 255. 4-F —NHCH₂—

H 256. 4-F —NHCH₂—

H 257. 3,4- diF —NHCH₂—

H 258. H —NHCH₂—

H 259. 4-F —NHCH₂—

H 260. 4-F —NHCH₂—

H 261. 3,4- diF —NH(CH₂)₂—

H 262. H —NH(CH₂)₂—

H 263. 4-F —NH(CH₂)₂—

H 264. 4-F —NH(CH₂)₂—

H 265. 3,4- diF —NHCH₂—

H 266. H —NHCH₂—

H 267. 4-F —NHCH₂—

H 268. 4-F —NHCH₂—

H 269. 4-F —NHCH₂—

H 270. 4-F —NHCH₂—

H 271. 4-F —NHCH₂—

H 272. 4-F —NHCH₂—

H

[1099] Although the pharmacological properties of the compounds ofFormulas I-IV vary with structural change, in general, activitypossessed by compounds of Formulas I-IV may be demonstrated in vivo. Thepharmacological properties of the compounds of this invention may beconfirmed by a number of pharmacological in vitro assays. Theexemplified pharmacological assays which follow have been carried outwith the compounds according to the invention and their salts. Compoundsof the present invention showed inhibition of KDR kinase at doses lessthan 50 μm.

Biological Evaluation HUVEC Proliferation Assay

[1100] Human Umbilical Vein Endothelial cells are purchased fromClonetics, Inc., as cryopreserved cells harvested from a pool of donors.These cells, at passage 1, are thawed and expanded in EBM-2 completemedium, until passage 2 or 3. The cells are trypsinized, washed inDMEM+10% FBS+antibiotics, and spun at 1000 rpm for 10 min. Prior tocentrifugation of the cells, a small amount is collected for a cellcount. After centrifugation, the medium is discarded, and the cells areresuspended in the appropriate volume of DMEM+10% FBS+antibiotics toachieve a concentration of 3×10⁵ cells/mL. Another cell count isperformed to confirm the cell concentration. The cells are diluted to3×10⁴ cells/mL in DMEM+10% FBS+antibiotics, and 100 μL of cells areadded to a 96-well plate. The cells are incubated at 37° C. for 22 h.

[1101] Prior to the completion of the incubation period, compounddilutions are prepared. Five-point, five-fold serial dilutions areprepared in DMSO, at concentrations 400-fold greater than the finalconcentrations desired. 2.5 μL of each compound dilution are dilutedfurther in a total of 1 mL DMEM+10% FBS+antibiotics (400×dilution).Medium containing 0.25% DMSO is also prepared for the 0 μM compoundsample. At the 22-hour timepoint, the medium is removed from the cells,and 100 μL of each compound dilution is added. The cells are incubatedat 37° C. for 2-3 h.

[1102] During the compound pre-incubation period, the growth factors arediluted to the appropriate concentrations. Solutions of DMEM+10%FBS+antibiotics, containing either VEGF or bFGF at the followingconcentrations: 50, 10, 2, 0.4, 0.08, and 0 ng/mL are prepared. For thecompound-treated cells, solutions of VEGF at 550 ng/mL or bFGF at 220ng/mL for 50 ng/mL or 20 ng/mL final concentrations, respectively, areprepared since 10 μL of each will be added to the cells (110 μL finalvolume). At the appropriate time after adding the compounds, the growthfactors are added. VEGF is added to one set of plates, while bFGF isadded to another set of plates. For the growth factor control curves,the media on wells B4-G6 of plates 1 and 2 are replaced with mediacontaining VEGF or bFGF at the varying concentrations (50-0 ng/mL). Thecells are incubated at 37° C. for an additional 72 h.

[1103] At the completion of the 72 h incubation period, the medium isremoved, and the cells are washed twice with PBS. After the second washwith PBS, the plates are tapped gently to remove excess PBS, and thecells are placed at −70° C. for at least 30 min. The cells are thawedand analyzed using the CyQuant fluorescent dye (Molecular ProbesC-7026), following the manufacturer's recommendations. The plates areread on a Victor/Wallac 1420 workstation at 485 nm/530 nm(excitation/emission). Raw data are collected and analyzed using a4-parameter fit equation in XLFit. IC₅₀ values are then determined.

[1104] The compounds of examples 16-17 20-21, 25-27, 29, 34-35, 39-42,45-46, 52, 54-57, 58-65, 212, 215 and 243-245 inhibited VEGF-stimulatedHUVEC. proliferation at a level below 50 nM.

Angiogenesis Model

[1105] To determine the effects of the present compounds on angiogenesisin vivo, selective compounds are tested in the rat cornealneovascularization micropocket model or the angiogenesis assay ofPassaniti, Lab. Invest., 67, 519-28 (1992).

Rat Corneal Neovascularization Micropocket Model

[1106] In Life Aspects: Female Sprague Dawley rats weighingapproximately 250 g were randomized into one of five treatment groups.Pretreatment with the vehicle or compound was administered orally, 24 hprior to surgery and continued once a day for seven additional days. Onthe day of surgery, the rats were temporarily anesthetized in anIsofluorane gas chamber (delivering 2.5 liters/min oxygen+5%Isofluorane). An othoscope was then placed inside the mouth of theanimal to visualize the vocal cords. A tip-blunted wire was advanced inbetween the vocal cords and used as a guide for the placement of anendotracheal Teflon tube (Small Parts Inc. TFE-standard Wall R-SWTT-18).A volume-controlled ventilator (Harvard Apparatus, Inc. Model 683) wasconnected to the endotracheal tube to deliver a mixture of oxygen and 3%Isofluorane. Upon achieving deep anesthesia, the whiskers were cut shortand the eye areas and eyes gently washed with Betadine soap and rinsedwith sterile saline. The corneas were irrigated with one to two drops ofProparacaine HCl ophthalmic topical anesthetic solution (0.5%) (Bauschand Lomb Pharmaceuticals, Tampa Fla.). The rat was then positioned underthe dissecting microscope and the corneal surface brought into focus. Avertical incision was made on the midline of the cornea using a diamondblade knife. A pocket was created by using fine scissors to separate theconnective tissue layers of the stroma, tunneling towards the limbus ofthe eye. The distance between the apex of the pocket and the limbus wasapproximately 1.5 mm. After the pocket had been made, the soakednitrocellulose disk filter (Gelman Sciences, Ann Arbor Mich.) wasinserted under the lip of the pocket. This surgical procedure wasperformed on both eyes. rHu-bFGF soaked disks were placed into the righteye, and the rHu-VEGF soaked disks were placed into the left eye.Vehicle soaked disks were placed in both eyes. The disk was pushed intoposition at the desired distance from the limbal vessels. Ophthalmicantibiotic ointment was applied to the eye to prevent drying andinfection. After seven days, the rats were euthanized by CO₂asphyxiation, and the eyes enucleated. The retinal hemisphere of the eyewas windowed to facilitate fixation, and the eye placed into formalinovernight.

[1107] Post Mortem Aspects: After twenty-four hours in fixative, thecorneal region of interest was dissected out from the eye, using fineforceps and a razorblade. The retinal hemisphere was trimmed off and thelens extracted and discarded. The corneal dome was bisected and thesuperfluous cornea trimmed off. The iris, conjunctiva and associatedlimbal glands were then carefully teased away. Final cuts were made togenerate a square 3×3 mm containing the disk, the limbus, and the entirezone of neovascularization.

[1108] Gross Image Recording: The corneal specimens were digitallyphotographed using a Sony CatsEye DKC5000 camera (A. G. Heinz, IrvineCalif.) mounted on a Nikon SMZ-U stereo microscope (A. G. Heinz). Thecorneas were submerged in distilled water and photographed viatrans-illumination at approximately 5.0 diameters magnification.

[1109] Image analysis: Numerical endpoints were generated using digitalmicrographs collected from the whole mount corneas after trimming andwere used for image analysis on the Metamorph image analysis system(Universal Imaging Corporation, West Chester Pa.). Three measurementswere taken: Disk placement distance from the limbus, number of vesselsintersecting a 2.0 mm perpendicular line at the midpoint of the diskplacement distance, and percent blood vessel area of the diffusiondetermined by thresholding.

[1110] General Formulations

[1111] 0.1% BSA in PBS vehicle: 0.025 g of BSA was added to 25.0 ml ofsterile 1× phosphate buffered saline, gently shaken until fullydissolved, and filtered at 0.2 μm. Individual 1.0 ml samples werealiquoted into 25 single use vials, and stored at −20° C. until use. Forthe rHu-bFGF disks, a vial of this 0.1% BSA solution was allowed to thawat room temperature. Once thawed, 10 μl of a 100 mM stock solution ofDTT was added to the 1 ml BSA vial to yield a final concentration of 1mM DTT in 0.1% BSA.

[1112] rHu-VEGF Dilutions:

[1113] Prior to the disk implant surgery, 23.8 μl of the 0.1% BSAvehicle above was added to a 10 μg rHu-VEGF lyophilized vial yielding afinal concentration of 10 μM.

[1114] rHu-bFGF: Stock concentration of 180 ng/μl:

[1115] R&D rHu- bFGF: Added 139 μl of the appropriate vehicle above tothe 25 μg vial lyophilized vial. 13.3 μl of the [180 ng/μl] stock vialand added 26.6 μl of vehicle to yield a final concentration of 3.75 μMconcentration.

[1116] Nitro-cellulose disk preparation: The tip of a 20-gauge needlewas cut off square and beveled with emery paper to create a punch. Thistip was then used to cut out ≅0.5 mm diameter disks from anitrocellulose filter paper sheet (Gelman Sciences). Prepared disks werethen placed into Eppendorf microfuge tubes containing solutions ofeither 0.1% BSA in PBS vehicle, 10 μM rHu-VEGF (R&D Systems,Minneapolis, Minn.), or 3.75 μM rHu-bFGF (R&D Systems, Minneapolis,Minn.) and allowed to soak for 45-60 min before use. Each nitrocellulosefilter disk absorbs approximately 0.1 μl of solution.

[1117] In the rat micropocket assay, compounds of the present inventionwill inhibit angiogenesis at a dose of less than 50 mg/kg/day.

Tumor Model

[1118] A431 cells (ATCC) are expanded in culture, harvested and injectedsubcutaneously into 5-8 week old female nude mice (CD1 nu/nu, CharlesRiver Labs) (n=5-15). Subsequent administration of compound by oralgavage (10-200 mpk/dose) begins anywhere from day 0 to day 29 post tumorcell challenge and generally continues either once or twice a day forthe duration of the experiment. Progression of tumor growth is followedby three dimensional caliper measurements and recorded as a function oftime. Initial statistical analysis is done by repeated measures analysisof variance (RMANOVA), followed by Scheffe post hoc testing for multiplecomparisons. Vehicle alone (Ora-Plus, pH 2.0) is the negative control.Compounds of the present invention are active at doses less than 150mpk.

Rat Adjuvant Arthritis Model

[1119] The rat adjuvant arthritis model (Pearson, Proc. Soc. Exp. Biol.91, 95-101 (1956)) is used to test the anti-arthritic activity ofcompounds of the Formula I-III, or salts thereof. Adjuvant Arthritis canbe treated using two different dosing schedules: either (i) startingtime of immunization with adjuvant (prophylactic dosing); or from day 15when the arthritic response is already established (therapeutic dosing).Preferably a therapeutic dosing schedule is used.

Rat Carrageenan-induced Analgesia Test

[1120] The rat carrageenan analgesia test was performed with materials,reagents and procedures essentially as described by Hargreaves, et al.,(Pain, 32, 77 (1988)). Male Sprague-Dawley rats were treated aspreviously described for the Carrageenan Foot Pad Edema test. Threehours after the injection of the carrageenan, the rats were placed in aspecial plexiglass container with a transparent floor having a highintensity lamp as a radiant heat source, positionable under the floor.After an initial twenty minute period, thermal stimulation was begun oneither the injected foot or on the contralateral uninjected foot. Aphotoelectric cell turned off the lamp and timer when light wasinterrupted by paw withdrawal. The time until the rat withdraws its footwas then measured. The withdrawal latency in seconds was determined forthe control and drug-treated groups, and percent inhibition of thehyperalgesic foot withdrawal determined.

[1121] Formulations

[1122] Also embraced within this invention is a class of pharmaceuticalcompositions comprising the active compounds of Formulas I-III inassociation with one or more non-toxic, pharmaceutically-acceptablecarriers and/or diluents and/or adjuvants (collectively referred toherein as “carrier” materials) and, if desired, other activeingredients. The active compounds of the present invention may beadministered by any suitable route, preferably in the form of apharmaceutical composition adapted to such a route, and in a doseeffective for the treatment intended. The compounds and compositions ofthe present invention may, for example, be administered orally,mucosally, topically, rectally, pulmonarily such as by inhalation spray,or parentally including intravascularly, intravenously,intraperitoneally, subcutaneously, intramuscularly intrasternally andinfusion techniques, in dosage unit formulations containing conventionalpharmaceutically acceptable carriers, adjuvants, and vehicles.

[1123] The pharmaceutically active compounds of this invention can beprocessed in accordance with conventional methods of pharmacy to producemedicinal agents for administration to patients, including humans andother mammals.

[1124] For oral administration, the pharmaceutical composition may be inthe form of, for example, a tablet, capsule, suspension or liquid. Thepharmaceutical composition is preferably made in the form of a dosageunit containing a particular amount of the active ingredient. Examplesof such dosage units are tablets or capsules. For example, these maycontain an amount of active ingredient from about 1 to 2000 mg,preferably from about 1 to 500 mg. A suitable daily dose for a human orother mammal may vary widely depending on the condition of the patientand other factors, but, once again, can be determined using routinemethods.

[1125] The amount of compounds which are administered and the dosageregimen for treating a disease condition with the compounds and/orcompositions of this invention depends on a variety of factors,including the age, weight, sex and medical condition of the subject, thetype of disease, the severity of the disease, the route and frequency ofadministration, and the particular compound employed. Thus, the dosageregimen may vary widely, but can be determined routinely using standardmethods. A daily dose of about 0.01 to 500 mg/kg body weight, preferablybetween about 0.1 and about 50 mg/kg body weight, may be appropriate.The daily dose can be administered in one to four doses per day.

[1126] For therapeutic purposes, the active compounds of this inventionare ordinarily combined with one or more adjuvants appropriate to theindicated route of administration. If administered per os, the compoundsmay be admixed with lactose, sucrose, starch powder, cellulose esters ofalkanoic acids, cellulose alkyl esters, talc, stearic acid, magnesiumstearate, magnesium oxide, sodium and calcium salts of phosphoric andsulfuric acids, gelatin, acacia gum, sodium alginate,polyvinylpyrrolidone, and/or polyvinyl alcohol, and then tableted orencapsulated for convenient administration. Such capsules or tablets maycontain a controlled-release formulation as may be provided in adispersion of active compound in hydroxypropylmethyl cellulose.

[1127] In the case of psoriasis and other skin conditions, it may bepreferable to apply a topical preparation of compounds of this inventionto the affected area two to four times a day.

[1128] Formulations suitable for topical administration include liquidor semi-liquid preparations suitable for penetration through the skin(e.g., liniments, lotions, ointments, creams, or pastes) and dropssuitable for administration to the eye, ear, or nose. A suitable topicaldose of active ingredient of a compound of the invention is 0.1 mg to150 mg administered one to four, preferably one or two times daily. Fortopical administration, the active ingredient may comprise from 0.001%to 10% w/w, e.g., from 1% to 2% by weight of the formulation, althoughit may comprise as much as 10% w/w, but preferably not more than 5% w/w,and more preferably from 0.1% to 1% of the formulation.

[1129] When formulated in an ointment, the active ingredients may beemployed with either paraffinic or a water-miscible ointment base.Alternatively, the active ingredients may be formulated in a cream withan oil-in-water cream base. If desired, the aqueous phase of the creambase may include, for example at least 30% w/w of a polyhydric alcoholsuch as propylene glycol, butane-1,3-diol, mannitol, sorbitol, glycerol,polyethylene glycol and mixtures thereof. The topical formulation maydesirably include a compound which enhances absorption or penetration ofthe active ingredient through the skin or other affected areas. Examplesof such dermal penetration enhancers include DMSO and related analogs.

[1130] The compounds of this invention can also be administered by atransdermal device. Preferably transdermal administration will beaccomplished using a patch either of the reservoir and porous membranetype or of a solid matrix variety. In either case, the active agent isdelivered continuously from the reservoir or microcapsules through amembrane into the active agent permeable adhesive, which is in contactwith the skin or mucosa of the recipient. If the active agent isabsorbed through the skin, a controlled and predetermined flow of theactive agent is administered to the recipient. In the case ofmicrocapsules, the encapsulating agent may also function as themembrane.

[1131] The oily phase of the emulsions of this invention may beconstituted from known ingredients in a known manner. While the phasemay comprise merely an emulsifier, it may comprise a mixture of at leastone emulsifier with a fat or an oil or with both a fat and an oil.Preferably, a hydrophilic emulsifier is included together with alipophilic emulsifier which acts as a stabilizer. It is also preferredto include both an oil and a fat. Together, the emulsifier(s) with orwithout stabilizer(s) make-up the so-called emulsifying wax, and the waxtogether with the oil and fat make up the so-called emulsifying ointmentbase which forms the oily dispersed phase of the cream formulations.Emulsifiers and emulsion stabilizers suitable for use in the formulationof the present invention include Tween 60, Span 80, cetostearyl alcohol,myristyl alcohol, glyceryl monostearate, sodium lauryl sulfate, glyceryldistearate alone or with a wax, or other materials well known in theart.

[1132] The choice of suitable oils or fats for the formulation is basedon achieving the desired cosmetic properties, since the solubility ofthe active compound in most oils likely to be used in pharmaceuticalemulsion formulations is very low. Thus, the cream should preferably bea non-greasy, non-staining and washable product with suitableconsistency to avoid leakage from tubes or other containers. Straight orbranched chain, mono- or dibasic alkyl esters such as di-isoadipate,isocetyl stearate, propylene glycol diester of coconut fatty acids,isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate,2-ethylhexyl palmitate or a blend of branched chain esters may be used.These may be used alone or in combination depending on the propertiesrequired. Alternatively, high melting point lipids such as white softparaffin and/or liquid paraffin or other mineral oils can be used.

[1133] Formulations suitable for topical administration to the eye alsoinclude eye drops wherein the active ingredients are dissolved orsuspended in suitable carrier, especially an aqueous solvent for theactive ingredients. The active ingredients are preferably present insuch formulations in a concentration of 0.5 to 20%, advantageously 0.5to 10% and particularly about 1.5% w/w.

[1134] Formulations for parenteral administration may be in the form ofaqueous or non-aqueous isotonic sterile injection solutions orsuspensions. These solutions and suspensions may be prepared fromsterile powders or granules using one or more of the carriers ordiluents mentioned for use in the formulations for oral administrationor by using other suitable dispersing or wetting agents and suspendingagents. The compounds may be dissolved in water, polyethylene glycol,propylene glycol, ethanol, corn oil, cottonseed oil, peanut oil, sesameoil, benzyl alcohol, sodium chloride, tragacanth gum, and/or variousbuffers. Other adjuvants and modes of administration are well and widelyknown in the pharmaceutical art. The active ingredient may also beadministered by injection as a composition with suitable carriersincluding saline, dextrose, or water, or with cyclodextrin (ie.Captisol), cosolvent solubilization (ie. propylene glycol) or micellarsolubilization (ie. Tween 80).

[1135] The sterile injectable preparation may also be a sterileinjectable solution or suspension in a non-toxic parenterally acceptablediluent or solvent, for example as a solution in 1,3-butanediol. Amongthe acceptable vehicles and solvents that may be employed are water,Ringer's solution, and isotonic sodium chloride solution. In addition,sterile, fixed oils are conventionally employed as a solvent orsuspending medium. For this purpose any bland fixed oil may be employed,including synthetic mono- or diglycerides. In addition, fatty acids suchas oleic acid find use in the preparation of injectables.

[1136] For pulmonary administration, the pharmaceutical composition maybe administered in the form of an aerosol or with an inhaler includingdry powder aerosol.

[1137] Suppositories for rectal administration of the drug can beprepared by mixing the drug with a suitable non-irritating excipientsuch as cocoa butter and polyethylene glycols that are solid at ordinarytemperatures but liquid at the rectal temperature and will thereforemelt in the rectum and release the drug.

[1138] The pharmaceutical compositions may be subjected to conventionalpharmaceutical operations such as sterilization and/or may containconventional adjuvants, such as preservatives, stabilizers, wettingagents, emulsifiers, buffers etc. Tablets and pills can additionally beprepared with enteric coatings. Such compositions may also compriseadjuvants, such as wetting, sweetening, flavoring, and perfuming agents.

[1139] The foregoing is merely illustrative of the invention and is notintended to limit the invention to the disclosed compounds. Variationsand changes which are obvious to one skilled in the art are intended tobe within the scope and nature of the invention which are defined in theappended claims.

[1140] From the foregoing description, one skilled in the art can easilyascertain the essential characteristics of this invention, and withoutdeparting from the spirit and scope thereof, can make various changesand modifications of the invention to adapt it to various usages andconditions.

[1141] All mentioned references, patents, applications and publications,are hereby incorporated by reference in their entirety, as if herewritten.

What is claimed is:
 1. Compound of Formula IV

wherein R² is selected from unsubstituted or substituted phenyl, and9-10 membered bicyclic and 11-14 membered tricyclic unsaturated orpartially unsaturated heterocyclyl, wherein substituted R² is optionallysubstituted with one or more substituents selected from halo,C₁₋₆-alkyl, optionally substituted C₃₋₆-cycloalkyl, optionallysubstituted phenyl, optionally substituted phenyl-C₁-C₄-alkylenyl,C₁₋₂-haloalkoxy, optionally substituted phenyloxy, optionallysubstituted 4-6 membered heterocyclyl-C₁-C₆-alkyl, optionallysubstituted 4-6 membered heterocyclyl-C₂-C₄-alkenyl, optionallysubstituted 4-6 membered heterocyclyl, optionally substituted 4-6membered heterocyclyloxy, optionally substituted 4-6 memberedheterocyclyl-C₁₋₄-alkoxy, optionally substituted 4-6 memberedheterocyclylsulfonyl, optionally substituted 4-6 memberedheterocyclylamino, optionally substituted 4-6 memberedheterocyclylcarbonyl, optionally substituted 4-6 memberedheterocyclyl-C₁₋₄-alkylcarbonyl, optionally substituted 4-6 memberedheterocyclylcarbonyl-C₁₋₄-alkyl, optionally substituted 4-6 memberedheterocyclyl-C₁₋₄-alkylcarbonylamino, optionally substituted 4-6membered heterocyclyl-oxycarbonylamino, C₁₋₂-haloalkyl, C₁₋₄-aminoalkyl,nitro, amino, C₁₋₃-alkylsulfonylamino, hydroxy, cyano, aminosulfonyl,C₁₋₂-alkylsulfonyl, halosulfonyl, C₁₋₄-alkylcarbonyl,amino-C₁₋₄-alkylcarbonyl, C₁₋₃-alkylamino-C₁₋₄-alkylcarbonyl,C₁₋₃-alkylamino-C₁₋₄-alkylcarbonylamino, C₁₋₄-alkoxycarbonyl-C₁₋₄-alkyl,C₁₋₃-alkylamino-C₁₋₃-alkyl, C-₁₋₃-alkylamino-C₁₋₃-alkoxy,C₁₋₃-alkylamino-C₁₋₃-alkoxy-C-₁₋₃-alkoxy, C-₁₋₄-alkoxycarbonyl,C₁₋₄-alkoxycarbonylamino-C-₁₋₄-alkyl,C₁₋₃-alkylsulfonylamino-C₁₋₃-alkoxy, C₁₋₄-hydroxyalkyl,

and C₁₋₄-alkoxy; wherein R^(e) and R^(f) are independently selected fromH and C₁₋₂-haloalkyl; wherein R^(g) is selected from H, C₁₋₃-alkyl,optionally substituted phenyl-C₁₋₃-alkyl, 4-6 membered heterocyclyl, andoptionally substituted 4-6 membered heterocyclyl-C₁-C₃-alkyl,C₁₋₃-alkoxy-C-₁₋₂-alkyl and C₁₋₃-alkoxy-C₁₋₃-alkoxy-C₁₋₃-alkyl; andwherein R⁸ is one or more substituents independently selected from halo,amino, nitro, hydroxy, C₁₋₆-alkyl, C₁₋₆-haloalkyl, C₁₋₆-alkoxy,C₁₋₆-haloalkoxy, C₁₋₆-aminoalkyl, C₁₋₆-hydroxyalkyl, optionallysubstituted phenyl, optionally substituted heterocyclyl, optionallysubstituted heterocyclyl-C₁₋₆-alkoxy, aminosulfonyl, C₃₋₆-cycloalkyl,C₁₋₆-alkylamino, C₁₋₆-alkylamino-C₁₋₆-alkyl, optionally substitutedheterocyclyl-C₁₋₆-alkylamino, optionally substitutedheterocyclyl-C₁₋₆-alkyl, C₁₋₆-alkylamino-C₂₋₄-alkynyl,C₁₋₆-alkylamino-C₁₋₆-alkoxy, C₁₋₆-alkylamino-C₁₋₆-alkoxy-C₁₋₆-alkoxy,and optionally substituted heterocyclyl-C₂₋₄-alkynyl; andpharmaceutically acceptable isomers and derivatives thereof; provided R²is not 3-trifluoromethylphenyl when R⁸ is 4-hydroxy or 3-hydroxy. 2.Compound of claim 1 wherein R² is selected from phenyl,1,2-dihydroquinolyl, 1,2,3,4-tetrahydro-isoquinolyl,1′,2′-dihydro-spiro[cyclopropane-1,3′-[3H]indol]-6′-yl, isoquinolyl,quinolyl, indolyl, isoindolyl, 2,3-dihydro-1H-indolyl, naphthyridinyl,1,2,3,4-tetrahydro-[1,8]naphthyridinyl, dihydrobenzo[1,4]oxaxinyl,quinozalinyl, benzo[d]isothiazolyl, 3,4-dihydro-quinazolinyl,2,3,4,4a,9,9a-hexahydro-1H-3-aza-fluorenyl,5,6,7-trihydro-1,2,4-triazolo[3,4-a]isoquinolyl, tetrahydroquinolinyl,indazolyl, 2,1,3-benzothiadiazolyl, benzodioxanyl, benzothienyl,benzofuryl, benzimidazolyl, dihydro-benzimidazolyl, benzoxazolyl andbenzthiazolyl, where R² is unsubstituted or substituted with one or moresubstituents selected from bromo, chloro, fluoro, iodo, nitro, amino,cyano, Boc-aminoethyl, hydroxy, oxo, fluorosulfonyl, methylsulfonyl,aminosulfonyl, 4-methylpiperazinylsulfonyl, cyclohexyl, phenyl,phenylmethyl, 4-pyridylmethyl, 4-morpholinylmethyl,1-methylpiperazin-4-ylmethyl, 1-methylpiperazin-4-ylpropyl,morpholinylpropyl, piperidin-1-ylmethyl, 1-methylpiperidin-4-ylmethyl,2-methyl-2-(1-methylpiperidin-4-yl)ethyl,2-methyl-2-(4-pyrimidinyl)ethyl,2-methyl-2-(5-methyloxadiazol-2-yl)ethyl,2-methyl-2-(pyrazol-5-yl)ethyl,2-methyl-2-(1-ethoxycarbonyl-1,2,3,6-tetrahydropyridin-4-yl)ethyl,morpholinylethyl, 1-(4-morpholinyl)-2,2-dimethylpropyl,1-(4-morpholinyl)-2,2-dimethylethyl, piperidin-4-ylethyl,1-Boc-piperidin-4-ylethyl, piperidin-1-ylethyl,1-Boc-piperidin-4-ylethyl, piperidin-4-ylmethyl,1-Boc-piperidin-4-ylmethyl, piperidin-4-ylpropyl,1-Boc-piperidin-4-ylpropyl, piperidin-1-ylpropyl, pyrrolidin-1-ylpropyl,pyrrolidin-2-ylpropyl, 1-Boc-pyrrolidin-2-ylpropyl,1-(pyrrolidin-1-yl)-2-methylpropyl, pyrrolidin-1-ylmethyl,pyrrolidin-2-ylmethyl, 1-Boc-pyrrolidin-2-ylmethyl,2-methyl-2-(pyrrolidin-1-yl)ethyl, pyrrolidinylpropenyl,pyrrolidinylbutenyl, methylcarbonyl, Boc, piperidin-1-ylmethylcarbonyl,pyrrolidin-1-yl-carbonyl, pyrrolidin-2-yl-carbonyl, 4-pyridylcarbonyl,4-methylpiperazin-1-ylcarbonylethyl, CH₃O—C(═O) —CH₂—, methoxycarbonyl,aminomethylcarbonyl, dimethylaminomethylcarbonyl, methylsulfonylamino,dimethylaminomethylcarbonylamino, 1-pyrrolidinyl-CH₂—C(═O)—NH—,4-morpholinyl-CH₂—C(═O)—NH—, 3-tetrahydrofuryl-O—C(═O)—NH—,cyclohexyl-N(CH₃)—, (4-pyrimidinyl)amino,(2-methylthio-4-pyrimidinyl)amino, 3-ethoxycarbonyl-2-methyl-fur-5-yl,4-methylpiperazin-1-yl, 4-methyl-1-piperidyl, 1-Boc-4-piperidyl,piperidin-4-yl, 1-methylpiperidin-4-yl,1-methyl-(1,2,3,6-tetrahydropyridyl), imidazolyl, morpholinyl,4-trifluoromethyl-1-piperidinyl, hydroxybutyl, methyl, ethyl, propyl,isopropyl, butyl, tert-butyl, sec-butyl, trifluoromethyl,pentafluoroethyl, nonafluorobutyl, dimethylaminopropyl,1,1-di(trifluoromethyl)-1-hydroxymethyl,1,1-di(trifluoromethyl)-1-(piperidinylethoxy)methyl,1,1-di(trifluoromethyl)-1-(pyrrolidin-2-ylmethoxy)methyl,1,1-di(trifluoromethyl)-1-(methoxyethoxyethoxy)methyl, 1-hydroxyethyl,2-hydroxyethyl, trifluoromethoxy, 1-aminoethyl, 2-aminoethyl,1-(N-isopropylamino)ethyl, 2-(N-isopropylamino)ethyl,3-tetrahydrofuryloxy, dimethylaminoethoxy, 4-chlorophenoxy, phenyloxy,azetidin-3-ylmethoxy, 1-Boc-azetidin-3-ylmethoxy,3-tetrahydrofurylmethoxy, pyrrolidin-2-ylmethoxy,1-methylcarbonyl-pyrrolidin-2-ylmethoxy, 1-Boc-pyrrolidin-2-ylmethoxy,pyrrolidin-1-ylmethoxy, 1-methyl-pyrrolidin-2-ylmethoxy,1-isopropyl-pyrrolidin-2-ylmethoxy, 1-Boc-piperdin-4-ylmethoxy,(1-pyrrolidinyl)ethoxy, piperdin-4-ylmethoxy, piperdin-3-ylmethoxy,1-methylpiperdin-4-yloxy, methylsulfonylaminoethoxy, isopropoxy, methoxyand ethoxy; and pharmaceutically acceptable isomers and derivativesthereof.
 3. Compound of claim 1 wherein R⁸ is one or more substituentsindependently selected from chloro, fluoro, bromo, hydroxy, methoxy,ethoxy, —O—CH₂—O—, trifluoromethoxy, 1-methylpiperidinylmethoxy,dimethylaminoethoxy, amino, dimethylamino, dimethylaminopropyl,diethylamino, aminosulfonyl, cyclohexyl, dimethylaminopropynyl,3-(4-morpholinyl)propyn-1-yl, dimethylaminoethoxyethoxy,3-(4-morpholinyl)propylamino, optionally substituted piperidinyl,morpholinyl, optionally substituted piperazinyl, optionally substitutedphenyl, methyl, ethyl, propyl, cyano, hydroxymethyl, aminomethyl andtrifluoromethyl; and pharmaceutically acceptable derivatives thereof. 4.Compound of claim 2 wherein R² is selected from1,2,3,4-tetrahydro-isoquinolyl optionally substituted with one or moresubstituents selected from methyl, and Boc, 1,2,3,4-tetrahydro-quinolyloptionally substituted with one or more substituents selected frommethyl, Boc and oxo, 2,3-dihydro-1H-indolyl optionally substituted withone or more substituents selected from methyl, methylsulfonyl,1-Boc-piperidin-4-ylmethyl, piperidin-4-ylmethyl, 1-Boc-piperidin-4-yl,piperidin-4-yl, 1-methyl-piperidin-4-ylmethyl, 1-methyl-piperidin-4-yl,pyrrolidin-1-yl-carbonyl, dimethylaminomethylcarbonyl,aminomethylcarbonyl, methylcarbonyl, pyrrolidin-2-ylmethyl, and1-Boc-pyrrolidin-2-ylmethyl, and 3,4-dihydro-2H-benzo[1,4]oxazinyloptionally substituted with one or more substituents selected frommethyl, and methylcarbonyl; and pharmaceutically acceptable derivativesthereof.
 5. Compound of claim 4 wherein R² is3,3-dimethyl-2,3-dihydro-1H-indolyl optionally substituted with asubstituent selected from pyrrolidin-1-yl-carbonyl, methylcarbonyl, andmethylsulfonyl; and pharmaceutically acceptable derivatives thereof. 6.Compound of claim 4 wherein R² is4,4-dimethyl-1,2,3,4-tetrahydro-1H-isoquinolinyl.
 7. Compound of claim 3wherein R⁸ is one or more substituents independently selected fromfluoro, hydroxy, amino, and nitro; and pharmaceutically acceptablederivatives thereof.
 8. Compound of claim 3 wherein R⁸ is 4-fluoro; andpharmaceutically acceptable derivatives thereof.
 9. Compound of claim 1wherein R² is selected from phenyl substituted with one or moresubstituents selected from chloro, tert-butyl, azetidin-3-ylmethoxy,1-Boc-azetidin-3-ylmethoxy, dimethylaminomethylcarbonylamino,1,1-di(trifluoromethyl)-1-(pyrrolidin-2-ylmethoxy)methyl,trifluoromethyl, 2-methyl-2-(morpholin-4-yl)ethyl,2-methyl-2-(pyrrolidin-1-yl)ethyl,2-methyl-2-(5-methyloxadiazol-2-yl)ethyl, methylsulfonylamino,1-methyl-pyrrolidin-2-ylmethoxy, and isopropyl; and pharmaceuticallyacceptable derivatives thereof.
 10. A compound and pharmaceuticallyacceptable salts thereof selected from:N-(3,3-Dimethyl-1-(methylsulfonyl)-2,3-dihydro-1H-indol-6-yl)-2-(((4-fluorophenyl)methyl)amino)-3-pyridinecarboxamide;N-(4-(1,1-dimethylethyl)-3-((N,N-dimethylglycyl)amino)phenyl)-2-(((4-fluorophenyl)methyl)amino)-3-pyridinecarboxamide;N-(3-((((2R)-1-methyl-2-pyrrolidinyl)methyl)oxy)-5-(trifluoromethyl)phenyl)-2-((3-(1,3-oxazol-5-yl)phenyl)amino)-3-pyridinecarboxamide;2-(((4-fluorophenyl)methyl)amino)-N-(3-((((2R)-1-methyl-2-pyrrolidinyl)methyl)oxy)-5-(trifluoromethyl)phenyl)-3-pyridinecarboxamide;2-(((4-fluorophenyl)methyl)amino)-N-(3-((methylsulfonyl)amino)-5-(trifluoromethyl)phenyl)-3-pyridinecarboxamide;2-((3-(1,3-oxazol-5-yl)phenyl)amino)-N-(3-(trifluoromethyl)phenyl)-3-pyridinecarboxamide;2-(((4-fluorophenyl)methyl)amino)-N-(4-(1-methyl-1-(5-methyl-1,3,4-oxadiazol-2-yl)ethyl)phenyl)-3-pyridinecarboxamide;3-(2-Chloro-5-{[2-(4-fluoro-benzylamino)-pyridine-3-carbonyl]-amino}-phenoxymethyl)-azetidine-1-carboxylicacid tert-butyl ester;N-[3-(Azetidin-3-ylmethoxy)-4-chloro-phenyl]-2-(4-fluoro-benzylamino)-nicotinamide;6-Chloro-3-(4-fluoro-benzylamino)-pyridazine-4-carboxylic acid(4-tert-butyl-phenyl)-amide;3-(4-Fluoro-benzylamino)-pyridazine-4-carboxylic acid(4-tert-butyl-phenyl)-amide;2-(4-Hydroxy-3-amino-benzylamino)-N-(4-isopropyl-phenyl)-nicotinamide;2-(4-Hydroxy-3-nitro-benzylamino)-N-(4-isopropyl-phenyl)-nicotinamide;3-(4-Fluoro-benzylamino)-1,2,5,6-tetrahydro-pyridazine-4-carboxylic acid(4-tert-butyl-phenyl)-amide; andN-[3-(Azetidin-3-ylmethoxy)-5-trifluoromethyl-phenyl]-2-(4-fluoro-benzylamino)-nicotinamide.11. A pharmaceutical composition comprising apharmaceutically-acceptable carrier and a compound as in any of claims1-10.
 12. A method of treating cancer in a subject, said methodcomprising administering an effective amount of a compound as in any ofclaims 1-10.
 13. The method of claim 12 comprising a combination with acompound selected from antibiotic-type agents, alkylating agents,antimetabolite agents, hormonal agents, immunological agents,interferon-type agents and miscellaneous agents.
 14. A method oftreating angiogenesis in a subject, said method comprising administeringan effective amount of a compound as in any of claims 1-10.
 15. Acompound as in any of claims 1-10 for use in a method of therapeutictreatment for the human or animal body.
 16. A method of treatingKDR-related disorders in a mammal, said method comprising administeringan effective amount of a compound as in any of claims 1-10.
 17. A methodof treating proliferation-related disorders in a mammal, said methodcomprising administering an effective amount of a compound as in any ofclaims 1-10.
 18. A method of reducing blood flow in a tumor in asubject, said method comprising administering an effective amount of acompound as in any of claims 1-10.
 19. A method of reducing tumor sizein a subject, said method comprising administering an effective amountof a compound as in any of claims 1-10.
 20. A method of treatingdiabetic retinopathy in a subject, said method comprising administeringan effective amount of a compound as in any of claims 1-10.